Therapeutic Agents Useful for Treating Pain

ABSTRACT

A compound of formula: 
     
       
         
         
             
             
         
       
     
     where Ar 1 , Ar 2 , X, R 3 , and m are as disclosed herein or a pharmaceutically acceptable salt thereof (a “Cycloheteroalkenyl Compound”); compositions comprising an effective amount of a Cycloheteroalkenyl Compound; and methods for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson&#39;s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, restricted brain function, Huntington&#39;s chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal comprising administering to an animal in need thereof an effective amount of a Cycloheteroalkenyl Compound are disclosed herein.

This application claims the benefit of U.S. provisional application No.60/489,516, filed Jul. 24, 2003, and International patent applicationno. PCT/US2004/023914, filed Jul. 23, 2004, the disclosure of eachapplication being incorporated by reference herein in its entirety.

1. FIELD OF THE INVENTION

The present invention relates to Cycloheteroalkenyl Compounds,compositions comprising an effective amount of a CycloheteroalkenylCompound and methods for treating or preventing a condition such as paincomprising administering to an animal in need thereof an effectiveamount of a Cycloheteroalkenyl Compound.

2. BACKGROUND OF THE INVENTION

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for 3 months or longer and can leadto significant changes in a patient's personality, lifestyle, functionalability and overall quality of life (K. M. Foley, Pain, in CecilTextbook of Medicine 100-107 (J. C. Bennett and F. Plum eds., 20th ed.1996)).

Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or cental nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at both Group I mGluRs (mGluR1 andmGluR5) (M. E. Fundytus, CNS Drugs 15:29-58 (2001)) and vanilloidreceptors (VR1) (V. Di Marzo et al., Current Opinion in Neurobiology12:372-379 (2002)) to pain processing. Inhibiting mGluR1 or mGluR5reduces pain, as shown by in vivo treatment with antibodies selectivefor either mGluR1 or mGluR5, where neuropathic pain in rats wasattenuated (M. E. Fundytus et al., NeuroReport 9:731-735 (1998)). It hasalso been shown that antisense oligonucleotide knockdown of mGluR1alleviates both neuropathic and inflammatory pain (M. E. Fundytus etal., British Journal of Pharmacology 132:354-367 (2001); M. E. Fundytuset al., Pharmacology, Biochemsitry & Behavior 73:401-410 (2002)). Smallmolecule antagonists for mGluR5-attenuated pain in in vivo animal modelsare disclosed in, e.g., K. Walker et al., Neuropharmacology 40:1-9(2000) and A. Dogrul et al., Neuroscience Letters 292:115-118 (2000)).

Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. Inaddition to the above-listed treatments, neuropathic pain, which can bedifficult to treat, has also been treated with anti-epileptics (e.g.gabapentin, carbamazepine, valproic acid, topiramate, phenyloin), NMDAantagonists (e.g. ketamine, dextromethorphan), topical lidocaine (forpost-herpetic neuralgia), and tricyclic antidepressants (e.g.fluoxetine, sertraline and amitriptyline).

Pain has been traditionally managed by administering non-opioidanalgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id.

Urinary incontinence (“UI”) is uncontrollable urination, generallycaused by bladder-detrusor-muscle instability. UI affects people of allages and levels of physical health, both in health care settings and inthe community at large. Physiologic bladder contraction results in largepart from acetylcholine-induced stimulation of post-ganglionicmuscarinic-receptor sites on bladder smooth muscle. Treatments for UIinclude the administration of drugs having bladder-relaxant properties,which help to control bladder-detrusor-muscle overactivity. For example,anticholinergics such as propantheline bromide and glycopyrrolate, andcombinations of smooth-muscle relaxants such as a combination of racemicoxybutynin and dicyclomine or an anticholinergic, have been used totreat UI (See, e.g., A. J. Wein, Urol. Clin. N. Am. 22:557-577 (1995);Levin et al., J. Urol. 128:396-398 (1982); Cooke et al., S. Afr. Med. J.63:3 (1983); R. K. Mirakhur et al., Anaesthesia 38:1195-1204 (1983)).These drugs are not effective, however, in all patients havinguninhibited bladder contractions. Administration of anticholinergicmedications represent the mainstay of this type of treatment.

None of the existing commercial drug treatments for UI has achievedcomplete success in all classes of UI patients, nor has treatmentoccurred without significant adverse side effects. For example,drowsiness, dry mouth, constipation, blurred vision, headaches,tachycardia, and cardiac arrhythmia, which are related to theanticholinergic activity of traditional anti-UI drugs, can occurfrequently and adversely affect patient compliance. Yet despite theprevalence of unwanted anticholinergic effects in many patients,anticholinergic drugs are currently prescribed for patients having UI.The Merck Manual of Medical Information 631-634 (R. Berkow ed., 1997).

Ulcers are sores occurring where the lining of the digestive tract hasbeen eroded by stomach acids or digestive juices. The sores aretypically well-defined round or oval lesions primarily occurring in thestomach and duodenum. About 1 in 10 people develop an ulcer. Ulcersdevelop as a result of an imbalance between acid-secretory factors, alsoknown as “aggressive factors,” such as stomach acid, pepsin, andHelicobacter pylori infection, and local mucosal-protective factors,such as secretion of bicarbonate, mucus, and prostaglandins.

Treatment of ulcers typically involves reducing or inhibiting theaggressive factors. For example, antacids such as aluminum hydroxide,magnesium hydroxide, sodium bicarbonate, and calcium bicarbonate can beused to neutralize stomach acids. Antacids, however, can causealkalosis, leading to nausea, headache, and weakness. Antacids can alsointerfere with the absorption of other drugs into the blood stream andcause diarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansoprazole are alsoused to treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Sucraflate is also used to treat ulcers. Sucraflate adheres toepithelial cells and is believed to form a protective coating at thebase of an ulcer to promote healing. Sucraflate, however, can causeconstipation, dry mouth, and interfere with the absorption of otherdrugs.

Antibiotics are used when Helicobacter pylori is the underlying cause ofthe ulcer. Often antibiotic therapy is coupled with the administrationof bismuth compounds such as bismuth subsalicylate and colloidal bismuthcitrate. The bismuth compounds are believed to enhance secretion ofmucous and HCO₃ ⁻, inhibit pepsin activity, and act as an antibacterialagainst H. pylori. Ingestion of bismuth compounds, however, can lead toelevated plasma concentrations of Bi⁺³ and can interfere with theabsorption of other drugs.

Prostaglandin analogues, such as misoprostal, inhibit secretion of acidand stimulate the secretion of mucous and bicarbonate and are also usedto treat ulcers, especially ulcers in patients who require nonsteroidalanti-inflammatory drugs. Effective oral doses of prostaglandinanalogues, however, can cause diarrhea and abdominal cramping. Inaddition, some prostaglandin analogues are abortifacients.

Carbenoxolone, a mineral corticoid, can also be used to treat ulcers.Carbenoxolone appears to alter the composition and quantity of mucous,thereby enhancing the mucosal barrier. Carbenoxolone, however, can leadto Na⁺ and fluid retention, hypertension, hypokalemia, and impairedglucose tolerance.

Muscarinic cholinergic antagonists such as pirenzapine and telenzapinecan also be used to reduce acid secretion and treat ulcers. Side effectsof muscarinic cholinergic antagonists include dry mouth, blurred vision,and constipation. The Merck Manual of Medical Information 496-500 (R.Berkow ed., 1997) and Goodman and Gilman's The Pharmacological Basis ofTherapeutics 901-915 (J. Hardman and L. Limbird eds., 9^(th) ed. 1996).

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which thebowel becomes inflamed, often causing recurring abdominal cramps anddiarrhea. The two types of IBD are Crohn's disease and ulcerativecolitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority start between the ages of 14 and 24. Thedisease typically affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Early symptoms of Crohn's disease are chronic diarrhea, crampy abdominalpain, fever, loss of appetite, and weight loss. Complications associatedwith Crohn's disease include the development of intestinal obstructions,abnormal connecting channels (fistulas), and abscesses. The risk ofcancer of the large intestine is increased in people who have Crohn'sdisease. Often Crohn's disease is associated with other disorders suchas gallstones, inadequate absorption of nutrients, amyloidosis,arthritis, episcleritis, aphthous stomatitis, erythema nodosum, pyodermagangrenosum, ankylosing spondylitis, sacroilitis, uveitis, and primarysclerosing cholangitis. There is no known cure for Crohn's disease.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine. Generally, the drug is takenorally before a meal.

Broad-spectrum antibiotics are often administered to treat the symptomsof Crohn's disease. The antibiotic metronidazole is often administeredwhen the disease affects the large intestine or causes abscesses andfistulas around the anus. Long-term use of metronidazole, however, candamage nerves, resulting in pins-and-needles sensations in the arms andlegs. Sulfasalazine and chemically related drugs can suppress mildinflammation, especially in the large intestine. These drugs, however,are less effective in sudden, severe flare-ups. Corticosteroids, such asprednisone, reduce fever and diarrhea and relieve abdominal pain andtenderness. Long-term corticosteroid therapy, however, invariablyresults in serious side effects such as high blood-sugar levels,increased risk of infection, osteoporosis, water retention, andfragility of the skin. Drugs such as azathioprine and mercaptourine cancompromise the immune system and are often effective for Crohn's diseasein patients that do not respond to other drugs. These drugs, however,usually need 3 to 6 months before they produce benefits and can causeserious side effects such as allergy, pancreatitis, and lowwhite-blood-cell count.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed. TheMerck Manual of Medical Information 528-530 (R. Berkow ed., 1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely throughout thelarge intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation,reducing symptoms, and replacing lost fluids and nutrients.Anticholinergic drugs and low doses of diphenoxylate or loperamide areadministered for treating mild diarrhea. For more intense diarrheahigher doses of diphenoxylate or loperamide, or deodorized opiumtincture or codeine are administered. Sulfasalazine, olsalazine,prednisone, or mesalamine can be used to reduce inflammation.Azathioprine and mercaptopurine have been used to maintain remissions inulcerative-colitis patients who would otherwise need long-termcorticosteroid treatment. In severe cases of ulcerative colitis thepatient is hospitalized and given corticosteroids intravenously. Peoplewith severe rectal bleeding can require transfusions and intravenousfluids. If toxic colitis develops and treatments fail, surgery to removethe large intestine can be necessary. Non-emergency surgery can beperformed if cancer is diagnosed, precancerous lesions are detected, orunremitting chronic disease would otherwise make the person an invalidor dependent on high doses of corticosteroids. Complete removal of thelarge intestine and rectum permanently cures ulcerative colitis. TheMerck Manual of Medical Information 530-532 (R. Berkow ed., 1997) andGoodman and Gilman's The Pharmacological Basis of Therapeutics (J.Hardman and L. Limbird eds., 9^(th) ed. 1996).

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entiregastrointestinal tract, causing abdominal pain, constipation, and/ordiarrhea. IBS affects three-times more women than men. In IBS stimulisuch as stress, diet, drugs, hormones, or irritants can cause thegastrointestinal tract to contract abnormally. During an episode of IBS,contractions of the gastrointestinal tract become stronger and morefrequent, resulting in the rapid transit of food and feces through thesmall intestine, often leading to diarrhea. Cramps result from thestrong contractions of the large intestine and increased sensitivity ofpain receptors in the large intestine.

There are two major types of IBS. The first type, spastic-colon type, iscommonly triggered by eating, and usually produces periodic constipationand diarrhea with pain. Mucous often appears in the stool. The pain cancome in bouts of continuous dull aching pain or cramps, usually in thelower abdomen. The person suffering from spastic-colon type IBS can alsoexperience bloating, gas, nausea, headache, fatigue, depression,anxiety, and difficulty concentrating. The second type of IBS usuallyproduces painless diarrhea or constipation. The diarrhea can beginsuddenly and with extreme urgency. Often the diarrhea occurs soon aftera meal and can sometimes occur immediately upon awakening.

Treatment of IBS typically involves modification of an IBS-patient'sdiet. Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS. Antidiarrheal drugs, such as diphenoxylateand loperamide, help with diarrhea. The Merck Manual of MedicalInformation 525-526 (R. Berkow ed., 1997).

Certain pharmaceutical agents have been administered for treatingaddiction. U.S. Pat. No. 5,556,838 to Mayer et al. discloses the use ofnontoxic NMDA-blocking agents co-administered with an addictivesubstance to prevent the development of tolerance or withdrawalsymptoms. U.S. Pat. No. 5,574,052 to Rose et al. disclosesco-administration of an addictive substance with an antagonist topartially block the pharmacological effects of the addictive substance.U.S. Pat. No. 5,075,341 to Mendelson et al. discloses the use of a mixedopiate agonist/antagonist to treat cocaine and opiate addiction. U.S.Pat. No. 5,232,934 to Downs discloses administration of3-phenoxypyridine to treat addiction. U.S. Pat. Nos. 5,039,680 and5,198,459 to Imperato et al. disclose using a serotonin antagonist totreat chemical addiction. U.S. Pat. No. 5,556,837 to Nestler et. al.discloses infusing BDNF or NT-4 growth factors to inhibit or reverseneurological adaptive changes that correlate with behavioral changes inan addicted individual. U.S. Pat. No. 5,762,925 to Sagan disclosesimplanting encapsulated adrenal medullary cells into an animal's centralnervous system to inhibit the development of opioid intolerance. U.S.Pat. No. 6,204,284 to Beer et al. discloses racemic(±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane for use in theprevention or relief of a withdrawal syndrome resulting from addictionto drugs and for the treatment of chemical dependencies.

Without treatment, Parkinson's disease progresses to a rigid akineticstate in which patients are incapable of caring for themselves. Deathfrequently results from complications of immobility, includingaspiration pneumonia or pulmonary embolism. Drugs commonly used for thetreatment of Parkinson's disease include carbidopa/levodopa, pergolide,bromocriptine, selegiline, amantadine, and trihexyphenidylhydrochloride. There remains, however, a need for drugs useful for thetreatment of Parkinson's disease and having an improved therapeuticprofile.

Currently, benzodiazepines are the most commonly used anti-anxietyagents for generalized anxiety disorder. Benzodiazepines, however, carrythe risk of producing impairment of cognition and skilled motorfunctions, particularly in the elderly, which can result in confusion,delerium, and falls with fractures. Sedatives are also commonlyprescribed for treating anxiety. The azapirones, such as buspirone, arealso used to treat moderate anxiety. The azapirones, however, are lessuseful for treating severe anxiety accompanied with panic attacks.

Examples of drugs for treating a seizure and epilepsy includecarbamazepine, ethosuximide, gabapentin, lamotrigine, phenobarbital,phenyloin, primidone, valproic acid, trimethadione, benzodiazepines,γ-vinyl GABA, acetazolamide, and felbamate. Anti-seizure drugs, however,can have side effects such as drowsiness; hyperactivity; hallucinations;inability to concentrate; central and peripheral nervous systemtoxicity, such as nystagmus, ataxia, diplopia, and vertigo; gingivalhyperplasia; gastrointestinal disturbances such as nausea, vomiting,epigastric pain, and anorexia; endocrine effects such as inhibition ofantidiuretic hormone, hyperglycemia, glycosuria, osteomalacia; andhypersensitivity such as scarlatiniform rash, morbilliform rash,Stevens-Johnson syndrome, systemic lupus erythematosus, and hepaticnecrosis; and hematological reactions such as red-cell aplasia,agranulocytosis, thrombocytopenia, aplastic anemia, and megaloblasticanemia. The Merck Manual of Medical Information 345-350 (R. Berkow ed.,1997).

Symptoms of strokes vary depending on what part of the brain isaffected. Symptoms include loss or abnormal sensations in an arm or legor one side of the body, weakness or paralysis of an arm or leg or oneside of the body, partial loss of vison or hearing, double vision,dizziness, slurred speech, difficulty in thinking of the appropriateword or saying it, inability to recognize parts of the body, unusualmovements, loss of bladder control, imbalance, and falling, andfainting. The symptoms can be permanent and can be associated with comaor stupor. Examples of drugs for treating strokes include anticoagulantssuch as heparin, drugs that break up clots such as streptokinase ortissue plasminogen activator, and drugs that reduce swelling such asmannitol or corticosteroids. The Merck Manual of Medical Information352-355 (R. Berkow ed., 1997).

Pruritus is an unpleasant sensation that prompts scratching.Conventionally, pruritus is treated by phototherapy with ultraviolet Bor PUVA or with therapeutic agents such as naltrexone, nalmefene,danazol, tricyclics, and antidepressants.

Selective antagonists of the metabotropic glutamate receptor 5(“mGluR5”) have been shown to exert analgesic activity in in vivo animalmodels (K. Walker et al., Neuropharmacology 40:1-9 (2000) and A. Dogrulet al., Neuroscience Letters, 292(2):115-118 (2000)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anxiolytic and anti-depressant activity in in vivo animal models(E. Tatarczynska et al., Br. J. Pharmacol. 132(7):1423-1430 (2001) andP. J. M. Will et al., Trends in Pharmacological Sciences 22(7):331-37(2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-Parkinson activity in vivo (K. J. Ossowska et al.,Neuropharmacology 41(4):413-20 (2001) and P. J. M. Will et al., Trendsin Pharmacological Sciences 22(7):331-37 (2001)).

Selective antagonists of the mGluR5 receptor have also been shown toexert anti-dependence activity in vivo (C. Chiamulera et al., NatureNeuroscience 4(9):873-74 (2001)).

International publication no. WO 97/28140 describes a class ofpiperidine compounds derived from1-(piperazin-1-yl)aryl(oxy/amino)carbonyl-4-aryl-piperidine that areuseful as 5-HT_(1Db) receptor antagonists.

International publication no. WO 98/31677 describes a class of aromaticamines derived from cyclic amines that are useful as antidepressantdrugs.

U.S. Pat. No. 4,797,419 to Moos et al. describes a class of ureacompounds for stimulating the release of acetylcholine and useful fortreating symptoms of senile cognitive decline.

Citation of any reference in Section 2 of this application is not to beconstrued as an admission that such reference is prior art to thepresent application.

3. SUMMARY OF THE INVENTION

The present invention encompasses compounds of formula (I):

and pharmaceutically acceptable salts thereof, where

Ar₁ is

Ar₂ is

X is O, S, N—CN, N—OH, or N—OR₁₀;

R₁ is —H, -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃,—CH(halo)₂, or —CH₂(halo);

each R₂ is independently:

-   -   (a)-halo, —OH, —NH₂, —CN, or —NO₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c)-phenyl, -naphthyl, —(C₁₄)aryl or -(5- to        10-membered)heteroaryl, each of which is unsubstituted or        substituted with one or more R₆ groups;

each R₃ is independently:

-   -   (a) -halo, —CN, —OH, —NO₂, or —NH₂;    -   (b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,        —(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl,        —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,        —(C₈-C₁₄)bicycloalkenyl, (C₈-C₁₄)tricycloalkenyl, -(3- to        7-membered)heterocycle, or -(7- to        10-membered)bicycloheterocycle, each of which is unsubstituted        or substituted with one or more R₅ groups; or    -   (c)-phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)        heteroaryl, each of which is unsubstituted or substituted with        one or more R₆ groups;

each R₅ is independently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₆ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, (C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, CH(halo)₂, —CH₂(halo), —CN, —OH,-halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇;

each R₇ is independently —H, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, -(3-to 5-membered)heterocycle, —C(halo)₃, —CH(halo)₂, or —CH₂(halo);

each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

R₁₀ is —(C₁-C₄)alkyl;

each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇;

each halo is independently —F, —Cl, —Br, or —I;

m is 0 or 1;

o is an integer ranging 0 to 4;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

s is an integer ranging from 0 to 4; and

r is an integer ranging from 0 to 5.

The invention further encompasses compounds of formula (II)

and pharmaceutically acceptable salts thereof, where

R₁ is -halo, —CH₃, —NO₂, —CN, —OH, —OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂,or —CH₂(halo);

X, R₂, R₃, Ar₂, and m are defined above for the compound of formula (I);and

n is an integer ranging from 0 to 3.

A compound of formula (I) or (II) or a pharmaceutically acceptable saltthereof (a “Cycloheteroalkenyl Compound”) is useful for treating orpreventing pain, UI, an ulcer, IBD, IBS, an addictive disorder,Parkinson's disease, parkinsonism, anxiety, epilepsy, stroke, a seizure,a pruritic condition, psychosis, a cognitive disorder, a memory deficit,restricted brain function, Huntington's chorea, ALS, dementia,retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, ordepression (each being a “Condition”) in an animal.

The invention also relates to compositions comprising an effectiveamount of a Cycloheteroalkenyl Compound and a pharmaceuticallyacceptable carrier or excipient. The compositions are useful fortreating or preventing a Condition in an animal.

The invention further relates to methods for treating a Condition,comprising administering to an animal in need thereof an effectiveamount of a Cycloheteroalkenyl Compound.

The invention further relates to methods for preventing a Condition,comprising administering to an animal in need thereof an effectiveamount of a Cycloheteroalkenyl Compound.

The invention still further relates to methods for inhibiting VanilloidReceptor 1 (“VR1”) function in a cell, comprising contacting a cellcapable of expressing VR1 with an effective amount of aCycloheteroalkenyl Compound.

The invention still further relates to methods for inhibiting mGluR5function in a cell, comprising contacting a cell capable of expressingmGluR5 with an effective amount of a Cycloheteroalkenyl Compound.

The invention still further relates to methods for inhibitingmetabotropic glutamate receptor 1 (“mGluR1”) function in a cell,comprising contacting a cell capable of expressing mGluR1 with aneffective amount of a Cycloheteroalkenyl Compound.

The invention still further relates to methods for preparing acomposition, comprising the step of admixing a CycloheteroalkenylCompound and a pharmaceutically acceptable carrier or excipient.

The invention still further relates to a kit comprising a containercontaining an effective amount of a Cycloheteroalkenyl Compound.

The present invention can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 CycloheteroalkenylCompounds of Formula (I)

As stated above, the present invention encompasses compounds of Formula(I)

and pharmaceutically acceptable salts thereof, where Ar₁, Ar₂, R₃, X,and m are defined above for the Cycloheteroalkenyl Compounds of formula(I).

In one embodiment, Ar₁ is a pyrimidyl group.

In another embodiment, Ar₁ is a pyrazinyl group.

In another embodiment, Ar₁ is a pyridazinyl group.

In another embodiment, Ar₁ is a thiadiazolyl group.

In another embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR₁₀.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, p is 0.

In another embodiment, p is 1.

In another embodiment, o is 0.

In another embodiment, o is 1.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, R₁ is —H.

In another embodiment, R₁ is -halo.

In another embodiment, R₁ is —CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, p is 1 and R₂ is -halo, —OH, —NH₂, —CN, or —NO₂.

In another embodiment, p is 1 and R₂ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicyclo alkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, p is 1 and R₂ is -phenyl, -naphthyl, —(C₁₋₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂;

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₋₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, Ar₂ is a benzothiazolyl group, benzoimidazolylgroup, or benzooxazolyl group and each R₈ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,—OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is a benzothiazolyl group and s is 1.

In another embodiment, Ar₂ is a benzoimidazolyl group and s is 1.

In another embodiment, Ar₂ is a benzooxazolyl group and s is 1.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —S(O)R₇, or—S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —CO₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and q is 1.

In another embodiment, Ar₂ is

and r is 1.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyrazinyl group, X is O, m is 0, and Ar₂is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyrimidinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a pyridazinyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzothiazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzooxazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is a benzoimidazolyl group.

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is

In another embodiment, Ar₁ is a thiadiazolyl group, X is O, m is 0, andAr₂ is

4.2 Cycloheteroalkenyl Compounds of Formula (II)

The invention also relates to Cycloheteroalkenyl Compounds of formula(II)

and pharmaceutically acceptable salts thereof, where R₁, R₂, R₃, Ar₂, X,n and m are defined above for the Cycloheteroalkenyl Compounds offormula (II).

In one embodiment, X is O.

In another embodiment, X is S.

In another embodiment, X is N—CN.

In another embodiment, X is N—OH.

In another embodiment, X is N—OR₁₀.

In another embodiment, Ar₂ is a benzoimidazolyl group.

In another embodiment, Ar₂ is a benzothiazolyl group.

In another embodiment, Ar₂ is a benzooxazolyl group.

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, Ar₂ is

In another embodiment, m is 0.

In another embodiment, m is 1.

In another embodiment, n is 0.

In another embodiment, n is 1.

In another embodiment, n is 2.

In another embodiment, n is 3.

In another embodiment, o is 0.

In another embodiment, o is 1.

In another embodiment, q is 0.

In another embodiment, q is 1.

In another embodiment, r is 0.

In another embodiment, r is 1.

In another embodiment, R₁ is -halo

In another embodiment, R₁-is CH₃.

In another embodiment, R₁ is —NO₂.

In another embodiment, R₁ is —CN.

In another embodiment, R₁ is —OH.

In another embodiment, R₁ is —OCH₃.

In another embodiment, R₁ is —NH₂.

In another embodiment, R₁ is —C(halo)₃.

In another embodiment, R₁ is —CH(halo)₂.

In another embodiment, R₁ is —CH₂(halo).

In another embodiment, n is 1 and R₂ is -halo, —OH, —NH₂, —CN, or —NO₂.

In another embodiment, n is 1 and R₂ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicyclo alkyl, —(C₈-C₁₄)tricyclo alkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, n is 1 and R₂ is -phenyl, -naphthyl, —(C₁₋₄)arylor -(5- to 10-membered)heteroaryl, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is -halo, —CN, —OH, —NO₂, or —NH₂;

In another embodiment, m is 1 and R₃ is —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups.

In another embodiment, m is 1 and R₃ is -phenyl, -naphthyl, —(C₁₋₄)arylor -(5- to 10-membered)heterocycle, each of which is unsubstituted orsubstituted with one or more R₆ groups.

In another embodiment, m is 1 and R₃ is —CH₃.

In another embodiment, Ar₂ is a benzothiazolyl group, benzoimidazolylgroup, or benzooxazolyl group and each R₈ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,—OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is a benzothiazolyl group and s is 1.

In another embodiment, Ar₂ is a benzoimidazolyl group and s is 1.

In another embodiment, Ar₂ is a benzooxazolyl group and s is 1.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇.

In another embodiment, Ar₂ is

and each R₈ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and o is 1.

In another embodiment, Ar₂ is

and q is 1.

In another embodiment, Ar₂ is

and r is 1.

In another embodiment, X is O, m is 0, and Ar₂ is a benzothiazolylgroup.

In another embodiment, X is O, m is 0, and Ar₂ is a benzooxazolyl group.

In another embodiment, X is O, m is 0, and Ar₂ is a benzoimidazolylgroup.

In another embodiment, X is O, m is 0, and Ar₂ is

In another embodiment, X is O, m is 0, and Ar₂ is

In the Cycloheteroalkenyl Compounds that have an R₃ group, the R₃ groupcan be attached to the carbon atom at the 2-, 3-, 5- or 6-position ofthe Cycloheteroalkenyl ring. In one embodiment, the R₃ group is attachedto the carbon at the 2-position of the Cycloheteroalkenyl ring. Inanother embodiment, the R₃ group is attached to the carbon at the3-position of the Cycloheteroalkenyl ring. In another embodiment, the R₃group is attached to the carbon at the 6-position of theCycloheteroalkenyl ring. In another embodiment, the R₃ group is attachedto the carbon at the 5-position of the Cycloheteroalkenyl ring.

In one embodiment, the Cycloheteroalkenyl Compound has an R₃ group; thecarbon atom to which the R₃ group is attached is at the 2-, 3- or6-position of the Cycloheteroalkenyl ring; and the carbon atom to whichthe R₃ group is attached has the (R) configuration. In anotherembodiment, the Cycloheteroalkenyl Compound has an R₃ group; the carbonatom to which the R₃ group is attached is at the 2-, 3- or 6-position ofthe Cycloheteroalkenyl ring; and the carbon atom to which the R₃ groupis attached has the (S) configuration.

In another embodiment, the Cycloheteroalkenyl Compound has an R₃ group,the R₃ group is attached to the carbon that is at the 2-position of theCycloheteroalkenyl ring, and the carbon to which the R₃ group isattached is in the (R) configuration. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon that is at the 2-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (R) configuration,and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cycloheteroalkenyl Compound hasan R₃ group, the R₃ group is attached to the carbon that is at the2-position of the Cycloheteroalkenyl ring, the carbon to which the R₃group is attached is in the (R) configuration, and R₃ is —CH₃. Inanother embodiment, the Cycloheteroalkenyl Compound has an R₃ group, theR₃ group is attached to the carbon that is at the 2-position of theCycloheteroalkenyl ring, the carbon to which the R₃ group is attached isin the (R) configuration, and R₃ is —CF₃. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon that is at the 2-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (R) configuration,and R₃ is —CH₂CH₃.

In another embodiment, the Cycloheteroalkenyl Compound has an R₃ group,the R₃ group is attached to the carbon atom at the 3-position of theCycloheteroalkenyl ring, and the carbon to which the R₃ group isattached is in the (R) configuration. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 3-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (R) configuration,and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cycloheteroalkenyl Compound hasan R₃ group, the R₃ group is attached to the carbon atom at the3-position of the Cycloheteroalkenyl ring, the carbon to which the R₃group is attached is in the (R) configuration, and R₃ is —CH₃. Inanother embodiment, the Cycloheteroalkenyl Compound has an R₃ group, theR₃ group is attached to the carbon atom at the 3-position of theCycloheteroalkenyl ring, the carbon to which the R₃ group is attached isin the (R) configuration, and R₃ is —CF₃. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 3-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (R) configuration,and R₃ is —CH₂CH₃.

In another embodiment, the Cycloheteroalkenyl Compound has an R₃ group,the R₃ group is attached to the carbon atom at the 6-position of theCycloheteroalkenyl ring, and the carbon to which the R₃ group isattached is in the (R) configuration. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 6-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (R) configuration,and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cycloheteroalkenyl Compound hasan R₃ group, the R₃ group is attached to the carbon atom at the6-position of the Cycloheteroalkenyl ring, the carbon to which the R₃group is attached is in the (R) configuration, and R₃ is —CH₃. Inanother embodiment, the Cycloheteroalkenyl Compound has an R₃ group, theR₃ group is attached to the carbon atom at the 6-position of theCycloheteroalkenyl ring, the carbon to which the R₃ group is attached isin the (R) configuration, and R₃ is —CF₃. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 6-position of the Cycloheteroalkenyl ring. The R₃group is in the (R) configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Cycloheteroalkenyl Compound has an R₃ group,the R₃ group is attached to the carbon that is at the 2-position of theCycloheteroalkenyl ring, and the carbon to which the R₃ group isattached is in the (S) configuration. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon that is at the 2-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (S) configuration,and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cycloheteroalkenyl Compound hasan R₃ group, the R₃ group is attached to the carbon that is at the2-position of the Cycloheteroalkenyl ring, the carbon to which the R₃group is attached is in the (S) configuration, and R₃ is —CH₃. Inanother embodiment, the Cycloheteroalkenyl Compound has an R₃ group, theR₃ group is attached to the carbon that is at the 2-position of theCycloheteroalkenyl ring, the carbon to which the R₃ group is attached isin the (S) configuration, and R₃ is —CF₃. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon that is at the 2-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (S) configuration,and R₃ is —CH₂CH₃.

In another embodiment, the Cycloheteroalkenyl Compound has an R₃ group,the R₃ group is attached to the carbon atom at the 3-position of theCycloheteroalkenyl ring, and the carbon to which the R₃ group isattached is in the (S) configuration. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 3-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (S) configuration,and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cycloheteroalkenyl Compound hasan R₃ group, the R₃ group is attached to the carbon atom at the3-position of the Cycloheteroalkenyl ring, the carbon to which the R₃group is attached is in the (S) configuration, and R₃ is —CH₃. Inanother embodiment, the Cycloheteroalkenyl Compound has an R₃ group, theR₃ group is attached to the carbon atom at the 3-position of theCycloheteroalkenyl ring, the carbon to which the R₃ group is attached isin the (S) configuration, and R₃ is —CF₃. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 3-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (S) configuration,and R₃ is —CH₂CH₃.

In another embodiment, the Cycloheteroalkenyl Compound has an R₃ group,the R₃ group is attached to the carbon atom at the 6-position of theCycloheteroalkenyl ring, and the carbon to which the R₃ group isattached is in the (S) configuration. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 6-position of the Cycloheteroalkenyl ring, thecarbon to which the R₃ group is attached is in the (S) configuration,and R₃ is —(C₁-C₄)alkyl unsubstituted or substituted with one or morehalo groups. In another embodiment, the Cycloheteroalkenyl Compound hasan R₃ group, the R₃ group is attached to the carbon atom at the6-position of the Cycloheteroalkenyl ring, the carbon to which the R₃group is attached is in the (S) configuration, and R₃ is —CH₃. Inanother embodiment, the Cycloheteroalkenyl Compound has an R₃ group, theR₃ group is attached to the carbon atom at the 6-position of theCycloheteroalkenyl ring, the carbon to which the R₃ group is attached isin the (S) configuration, and R₃ is —CF₃. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 6-position of the Cycloheteroalkenyl ring, thecarbon atom to which the R₃ group is attached is in the (S)configuration, and R₃ is —CH₂CH₃.

In another embodiment, the Cycloheteroalkenyl Compound has an R₃ group,the R₃ group is attached to the carbon atom at the 5-position of theCycloheteroalkenyl ring and R₃ is —(C₁-C₄) alkyl unsubstituted orsubstituted with one or more halo groups. In another embodiment, theCycloheteroalkenyl Compound has an R₃ group, the R₃ group is attached tothe carbon atom at the 5-position of the Cycloheteroalkenyl ring and R₃is —CH₃. In another embodiment, the Cycloheteroalkenyl Compound has anR₃ group, the R₃ group is attached to the carbon atom at the 5-positionof the Cycloheteroalkenyl ring and R₃ is —CF₃. In another embodiment,the Cycloheteroalkenyl Compound has an R₃ group, the R₃ group isattached to the carbon atom at the 5-position of the Cycloheteroalkenylring and R₃ is —CH₂CH₃.

Illustrative Cycloheteroalkenyl Compounds are listed below in Tables1-10:

TABLE 1 (Ia)

Compound R₁ R₈ A01(a), (b), and (c) —H —H A02(a), (b), and (c) —H-tent-butyl A03(a), (b), and (c) —H -iso-butyl A04(a), (b), and (c) —H-sec-butyl A05(a), (b), and (c) —H -iso-propyl A06(a), (b), and (c) —H-n-propyl A07(a), (b), and (c) —H -cyclohexyl A08(a), (b), and (c) —H-tert-butoxy A09(a), (b), and (c) —H -iso-propoxy A10(a), (b), and (c)—H —CF₃ A11(a), (b), and (c) —H —CH₂CF₃ A12(a), (b), and (c) —H —OCF₃A13(a), (b), and (c) —H —Cl A14(a), (b), and (c) —H —Br A15(a), (b), and(c) —H —I A16(a), (b), and (c) —H -n-butyl A17(a), (b), and (c) —H-n-propyl A18(a), (b), and (c) —Cl —H A19(a), (b), and (c) —Cl-tert-butyl A20(a), (b), and (c) —Cl -iso-butyl A21(a), (b), and (c) —Cl-sec-butyl A22(a), (b), and (c) —Cl -iso-propyl A23(a), (b), and (c) —Cl-n-propyl A24(a), (b), and (c) —Cl -cyclohexyl A25(a), (b), and (c) —Cl-tert-butoxy A26(a), (b), and (c) —Cl -iso-propoxy A27(a), (b), and (c)—Cl —CF₃ A28(a), (b), and (c) —Cl —CH₂CF₃ A29(a), (b), and (c) —Cl —OCF₃A30(a), (b), and (c) —Cl —Cl A31(a), (b), and (c) —Cl —Br A32(a), (b),and (c) —Cl —I A33(a), (b), and (c) —Cl -n-butyl A34(a), (b), and (c)—Cl -n-propyl A35(a), (b), and (c) —F —H A36(a), (b), and (c) —F-tent-butyl A37(a), (b), and (c) —F -iso-butyl A38(a), (b), and (c) —F-sec-butyl A39(a), (b), and (c) —F -iso-propyl A40(a), (b), and (c) —F-n-propyl A41(a), (b), and (c) —F -cyclohexyl A42(a), (b), and (c) —F-tert-butoxy A43(a), (b), and (c) —F -iso-propoxy A44(a), (b), and (c)—F —CF₃ A45(a), (b), and (c) —F —CH₂CF₃ A46(a), (b), and (c) —F —OCF₃A47(a), (b), and (c) —F —Cl A48(a), (b), and (c) —F —Br A49(a), (b), and(c) —F —I A50(a), (b), and (c) —F -n-butyl A51(a), (b), and (c) —F-n-propyl A52(a), (b), and (c) —CH₃ —H A53(a), (b), and (c) —CH₃-iso-butyl A54(a), (b), and (c) —CH₃ -tert-butyl A55(a), (b), and (c)—CH₃ -sec-butyl A56(a), (b), and (c) —CH₃ -iso-propyl A57(a), (b), and(c) —CH₃ -n-propyl A58(a), (b), and (c) —CH₃ -cyclohexyl A59(a), (b),and (c) —CH₃ -tert-butoxy A60(a), (b), and (c) —CH₃ -iso-propoxy A61(a),(b), and (c) —CH₃ —CF₃ A62(a), (b), and (c) —CH₃ —CH₂CF₃ A63(a), (b),and (c) —CH₃ —OCF₃ A64(a), (b), and (c) —CH₃ —Cl A65(a), (b), and (c)—CH₃ —Br A66(a), (b), and (c) —CH₃ —I A67(a), (b), and (c) —CH₃ -n-butylA68(a), (b), and (c) —CH₃ -n-propyl A69(a), (b), and (c) —CF₃ —H A70(a),(b), and (c) —CF₃ -tert-butyl A71(a), (b), and (c) —CF₃ -iso-butylA72(a), (b), and (c) —CF₃ -sec-butyl A73(a), (b), and (c) —CF₃-iso-propyl A74(a), (b), and (c) —CF₃ -n-propyl A75(a), (b), and (c)—CF₃ -cyclohexyl A76(a), (b), and (c) —CF₃ -tert-butoxy A77(a), (b), and(c) —CF₃ -iso-propoxy A78(a), (b), and (c) —CF₃ —CF₃ A79(a), (b), and(c) —CF₃ —CH₂CF₃ A80(a), (b), and (c) —CF₃ —OCF₃ A81(a), (b), and (c)—CF₃ —Cl A82(a), (b), and (c) —CF₃ —Br A83(a), (b), and (c) —CF₃ —IA84(a), (b), and (c) —CF₃ -n-butyl A85(a), (b), and (c) —CF₃ -n-propylA86(a), (b), and (c) —CHF₂ -tert-butyl A87(a), (b), and (c) —CHF₂ —HA88(a), (b), and (c) —CHF₂ -iso-butyl A89(a), (b), and (c) —CHF₂-sec-butyl A90(a), (b), and (c) —CHF₂ -iso-propyl A91(a), (b), and (c)—CHF₂ -n-propyl A92(a), (b), and (c) —CHF₂ -cyclohexyl A93(a), (b), and(c) —CHF₂ -tert-butoxy A94(a), (b), and (c) —CHF₂ -iso-propoxy A95(a),(b), and (c) —CHF₂ —CF₃ A96(a), (b), and (c) —CHF₂ —CH₂CF₃ A97(a), (b),and (c) —CHF₂ —OCF₃ A98(a), (b), and (c) —CHF₂ —Cl A99(a), (b), and (c)—CHF₂ —Br A100(a), (b), and (c) —CHF₂ —I A101(a), (b), and (c) —CHF₂-n-butyl A102(a), (b), and (c) —CHF₂ -n-propyl A103(a), (b), and (c) —OH—H A104(a), (b), and (c) —OH -tert-butyl A105(a), (b), and (c) —OH-iso-butyl A106(a), (b), and (c) —OH -sec-butyl A107(a), (b), and (c)—OH -iso-propyl A108(a), (b), and (c) —OH -n-propyl A109(a), (b), and(c) —OH -cyclohexyl A110(a), (b), and (c) —OH -tert-butoxy A111(a), (b),and (c) —OH -iso-propoxy A112(a), (b), and (c) —OH —CF₃ A113(a), (b),and (c) —OH —CH₂CF₃ A114(a), (b), and (c) —OH —OCF₃ A115(a), (b), and(c) —OH —Cl A116(a), (b), and (c) —OH —Br A117(a), (b), and (c) —OH —IA118(a), (b), and (c) —OH -n-butyl A119(a), (b), and (c) —OH -n-propylA120(a), (b), and (c) —NO₂ —H A121(a), (b), and (c) —NO₂ -tert-butylA122(a), (b), and (c) —NO₂ -iso-butyl A123(a), (b), and (c) —NO₂-sec-butyl A124(a), (b), and (c) —NO₂ -iso-propyl A125(a), (b), and (c)—NO₂ -n-propyl A126(a), (b), and (c) —NO₂ -cyclohexyl A127(a), (b), and(c) —NO₂ -tert-butoxy A128(a), (b), and (c) —NO₂ -iso-propoxy A129(a),(b), and (c) —NO₂ —CF₃ A130(a), (b), and (c) —NO₂ —CH₂CF₃ A131(a), (b),and (c) —NO₂ —OCF₃ A132(a), (b), and (c) —NO₂ —Cl A133(a), (b), and (c)—NO₂ —Br A134(a), (b), and (c) —NO₂ —I A135(a), (b), and (c) —NO₂-n-butyl A136(a), (b), and (c) —NO₂ -n-propyl A137(a), (b), and (c) —CN—H A138(a), (b), and (c) —CN -tert-butyl A139(a), (b), and (c) —CN-iso-butyl A140(a), (b), and (c) —CN -sec-butyl A141(a), (b), and (c)—CN -iso-propyl A142(a), (b), and (c) —CN -n-propyl A143(a), (b), and(c) —CN -cyclohexyl A144(a), (b), and (c) —CN -tert-butoxy A145(a), (b),and (c) —CN -iso-propoxy A146(a), (b), and (c) —CN —CF₃ A147(a), (b),and (c) —CN —CH₂CF₃ A148(a), (b), and (c) —CN —OCF₃ A149(a), (b), and(c) —CN —Cl A150(a), (b), and (c) —CN —Br A151(a), (b), and (c) —CN —IA152(a), (b), and (c) —CN -n-butyl A153(a), (b), and (c) —CN -n-propylA154(a), (b), and (c) —Br —H A155(a), (b), and (c) —Br -tert-butylA156(a), (b), and (c) —Br -iso-butyl A157(a), (b), and (c) —Br-sec-butyl A158(a), (b), and (c) —Br -iso-propyl A159(a), (b), and (c)—Br -n-propyl A160(a), (b), and (c) —Br -cyclohexyl A161(a), (b), and(c) —Br -tert-butoxy A162(a), (b), and (c) —Br -iso-propoxy A163(a),(b), and (c) —Br —CF₃ A164(a), (b), and (c) —Br —CH₂CF₃ A165(a), (b),and (c) —Br —OCF₃ A166(a), (b), and (c) —Br —Cl A167(a), (b), and (c)—Br —Br A168(a), (b), and (c) —Br —I A169(a), (b), and (c) —Br -n-butylA170(a), (b), and (c) —Br -n-propyl A171(a), (b), and (c) —I -tert-butylA172(a), (b), and (c) —I —H A173(a), (b), and (c) —I -iso-butyl A174(a),(b), and (c) —I -sec-butyl A175(a), (b), and (c) —I -iso-propyl A176(a),(b), and (c) —I -n-propyl A177(a), (b), and (c) —I -cyclohexyl A178(a),(b), and (c) —I -tert-butoxy A179(a), (b), and (c) —I -iso-propoxyA180(a), (b), and (c) —I —CF₃ A181(a), (b), and (c) —I —CH₂CF₃ A182(a),(b), and (c) —I —OCF₃ A183(a), (b), and (c) —I —Cl A184(a), (b), and (c)—I —Br A185(a), (b), and (c) —I —I A186(a), (b), and (c) —I -n-butylA187(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is—CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ andR₁₄ are each —H.

TABLE 2 (Ib)

Compound R₁ R₈ B01(a), (b), and (c) —H —H B02(a), (b), and (c) —H-tert-butyl B03(a), (b), and (c) —H -iso-butyl B04(a), (b), and (c) —H-sec-butyl B05(a), (b), and (c) —H -iso-propyl B06(a), (b), and (c) —H-n-propyl B07(a), (b), and (c) —H -cyclohexyl B08(a), (b), and (c) —H-tert-butoxy B09(a), (b), and (c) —H -iso-propoxy B10(a), (b), and (c)—H —CF₃ B11(a), (b), and (c) —H —CH₂CF₃ B12(a), (b), and (c) —H —OCF₃B13(a), (b), and (c) —H —Cl B14(a), (b), and (c) —H —Br B15(a), (b), and(c) —H —I B16(a), (b), and (c) —H -n-butyl B17(a), (b), and (c) —H-n-propyl B18(a), (b), and (c) —Cl —H B19(a), (b), and (c) —Cl-tert-butyl B20(a), (b), and (c) —Cl -iso-butyl B21(a), (b), and (c) —Cl-sec-butyl B22(a), (b), and (c) —Cl -iso-propyl B23(a), (b), and (c) —Cl-n-propyl B24(a), (b), and (c) —Cl -cyclohexyl B25(a), (b), and (c) —Cl-tert-butoxy B26(a), (b), and (c) —Cl -iso-propoxy B27(a), (b), and (c)—Cl —CF₃ B28(a), (b), and (c) —Cl —CH₂CF₃ B29(a), (b), and (c) —Cl —OCF₃B30(a), (b), and (c) —Cl —Cl B31(a), (b), and (c) —Cl —Br B32(a), (b),and (c) —Cl —I B33(a), (b), and (c) —Cl -n-butyl B34(a), (b), and (c)—Cl -n-propyl B35(a), (b), and (c) —F —H B36(a), (b), and (c) —F-tert-butyl B37(a), (b), and (c) —F -iso-butyl B38(a), (b), and (c) —F-sec-butyl B39(a), (b), and (c) —F -iso-propyl B40(a), (b), and (c) —F-n-propyl B41(a), (b), and (c) —F -cyclohexyl B42(a), (b), and (c) —F-tert-butoxy B43(a), (b), and (c) —F -iso-propoxy B44(a), (b), and (c)—F —CF₃ B45(a), (b), and (c) —F —CH₂CF₃ B46(a), (b), and (c) —F —OCF₃B47(a), (b), and (c) —F —Cl B48(a), (b), and (c) —F —Br B49(a), (b), and(c) —F —I B50(a), (b), and (c) —F -n-butyl B51(a), (b), and (c) —F-n-propyl B52(a), (b), and (c) —CH₃ —H B53(a), (b), and (c) —CH₃-iso-butyl B54(a), (b), and (c) —CH₃ -tert-butyl B55(a), (b), and (c)—CH₃ -sec-butyl B56(a), (b), and (c) —CH₃ -iso-propyl B57(a), (b), and(c) —CH₃ -n-propyl B58(a), (b), and (c) —CH₃ -cyclohexyl B59(a), (b),and (c) —CH₃ -tert-butoxy B60(a), (b), and (c) —CH₃ -iso-propoxy B61(a),(b), and (c) —CH₃ —CF₃ B62(a), (b), and (c) —CH₃ —CH₂CF₃ B63(a), (b),and (c) —CH₃ —OCF₃ B64(a), (b), and (c) —CH₃ —Cl B65(a), (b), and (c)—CH₃ —Br B66(a), (b), and (c) —CH₃ —I B67(a), (b), and (c) —CH₃ -n-butylB68(a), (b), and (c) —CH₃ -n-propyl B69(a), (b), and (c) —CF₃ —H B70(a),(b), and (c) —CF₃ -tert-butyl B71(a), (b), and (c) —CF₃ -iso-butylB72(a), (b), and (c) —CF₃ -sec-butyl B73(a), (b), and (c) —CF₃-iso-propyl B74(a), (b), and (c) —CF₃ -n-propyl B75(a), (b), and (c)—CF₃ -cyclohexyl B76(a), (b), and (c) —CF₃ -tert-butoxy B77(a), (b), and(c) —CF₃ -iso-propoxy B78(a), (b), and (c) —CF₃ —CF₃ B79(a), (b), and(c) —CF₃ —CH₂CF₃ B80(a), (b), and (c) —CF₃ —OCF₃ B81(a), (b), and (c)—CF₃ —Cl B82(a), (b), and (c) —CF₃ —Br B83(a), (b), and (c) —CF₃ —IB84(a), (b), and (c) —CF₃ -n-butyl B85(a), (b), and (c) —CF₃ -n-propylB86(a), (b), and (c) —CHF₂ -tert-butyl B87(a), (b), and (c) —CHF₂ —HB88(a), (b), and (c) —CHF₂ -iso-butyl B89(a), (b), and (c) —CHF₂-sec-butyl B90(a), (b), and (c) —CHF₂ -iso-propyl B91(a), (b), and (c)—CHF₂ -n-propyl B92(a), (b), and (c) —CHF₂ -cyclohexyl B93(a), (b), and(c) —CHF₂ -tert-butoxy B94(a), (b), and (c) —CHF₂ -iso-propoxy B95(a),(b), and (c) —CHF₂ —CF₃ B96(a), (b), and (c) —CHF₂ —CH₂CF₃ B97(a), (b),and (c) —CHF₂ —OCF₃ B98(a), (b), and (c) —CHF₂ —Cl B99(a), (b), and (c)—CHF₂ —Br B100(a), (b), and (c) —CHF₂ —I B101(a), (b), and (c) —CHF₂-n-butyl B102(a), (b), and (c) —CHF₂ -n-propyl B103(a), (b), and (c) —OH—H B104(a), (b), and (c) —OH -tert-butyl B105(a), (b), and (c) —OH-iso-butyl B106(a), (b), and (c) —OH -sec-butyl B107(a), (b), and (c)—OH -iso-propyl B108(a), (b), and (c) —OH -n-propyl B109(a), (b), and(c) —OH -cyclohexyl B110(a), (b), and (c) —OH -tert-butoxy B111(a), (b),and (c) —OH -iso-propoxy B112(a), (b), and (c) —OH —CF₃ B113(a), (b),and (c) —OH —CH₂CF₃ B114(a), (b), and (c) —OH —OCF₃ B115(a), (b), and(c) —OH —Cl B116(a), (b), and (c) —OH —Br B117(a), (b), and (c) —OH —IB118(a), (b), and (c) —OH -n-butyl B119(a), (b), and (c) —OH -n-propylB120(a), (b), and (c) —NO₂ —H B121(a), (b), and (c) —NO₂ -tert-butylB122(a), (b), and (c) —NO₂ -iso-butyl B123(a), (b), and (c) —NO₂-sec-butyl B124(a), (b), and (c) —NO₂ -iso-propyl B125(a), (b), and (c)—NO₂ -n-propyl B126(a), (b), and (c) —NO₂ -cyclohexyl B127(a), (b), and(c) —NO₂ -tert-butoxy B128(a), (b), and (c) —NO₂ -iso-propoxy B129(a),(b), and (c) —NO₂ —CF₃ B130(a), (b), and (c) —NO₂ —CH₂CF₃ B131(a), (b),and (c) —NO₂ —OCF₃ B132(a), (b), and (c) —NO₂ —Cl B133(a), (b), and (c)—NO₂ —Br B134(a), (b), and (c) —NO₂ —I B135(a), (b), and (c) —NO₂-n-butyl B136(a), (b), and (c) —NO₂ -n-propyl B137(a), (b), and (c) —CN—H B138(a), (b), and (c) —CN -tert-butyl B139(a), (b), and (c) —CN-iso-butyl B140(a), (b), and (c) —CN -sec-butyl B141(a), (b), and (c)—CN -iso-propyl B142(a), (b), and (c) —CN -n-propyl B143(a), (b), and(c) —CN -cyclohexyl B144(a), (b), and (c) —CN -tert-butoxy B145(a), (b),and (c) —CN -iso-propoxy B146(a), (b), and (c) —CN —CF₃ B147(a), (b),and (c) —CN —CH₂CF₃ B148(a), (b), and (c) —CN —OCF₃ B149(a), (b), and(c) —CN —Cl B150(a), (b), and (c) —CN —Br B151(a), (b), and (c) —CN —IB152(a), (b), and (c) —CN -n-butyl B153(a), (b), and (c) —CN -n-propylB154(a), (b), and (c) —Br —H B155(a), (b), and (c) —Br -tent-butylB156(a), (b), and (c) —Br -iso-butyl B157(a), (b), and (c) —Br-sec-butyl B158(a), (b), and (c) —Br -iso-propyl B159(a), (b), and (c)—Br -n-propyl B160(a), (b), and (c) —Br -cyclohexyl B161(a), (b), and(c) —Br -tert-butoxy B162(a), (b), and (c) —Br -iso-propoxy B163(a),(b), and (c) —Br —CF₃ B164(a), (b), and (c) —Br —CH₂CF₃ B165(a), (b),and (c) —Br —OCF₃ B166(a), (b), and (c) —Br —Cl B167(a), (b), and (c)—Br —Br B168(a), (b), and (c) —Br —I B169(a), (b), and (c) —Br -n-butylB170(a), (b), and (c) —Br -n-propyl B171(a), (b), and (c) —I -tent-butylB172(a), (b), and (c) —I —H B173(a), (b), and (c) —I -iso-butyl B174(a),(b), and (c) —I -sec-butyl B175(a), (b), and (c) —I -iso-propyl B176(a),(b), and (c) —I -n-propyl B177(a), (b), and (c) —I -cyclohexyl B178(a),(b), and (c) —I -tert-butoxy B179(a), (b), and (c) —I -iso-propoxyB180(a), (b), and (c) —I —CF₃ B181(a), (b), and (c) —I —CH₂CF₃ B182(a),(b), and (c) —I —OCF₃ B183(a), (b), and (c) —I —Cl B184(a), (b), and (c)—I —Br B185(a), (b), and (c) —I —I B186(a), (b), and (c) —I -n-butylB187(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is—CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ andR₁₄ are each —H.

TABLE 3 (Ic)

Compound R₁ R₈ C01(a), (b), and (c) —H —H C02(a), (b), and (c) —H-tert-butyl C03(a), (b), and (c) —H -iso-butyl C04(a), (b), and (c) —H-sec-butyl C05(a), (b), and (c) —H -iso-propyl C06(a), (b), and (c) —H-n-propyl C07(a), (b), and (c) —H -cyclohexyl C08(a), (b), and (c) —H-tert-butoxy C09(a), (b), and (c) —H -iso-propoxy C10(a), (b), and (c)—H —CF₃ C11(a), (b), and (c) —H —CH₂CF₃ C12(a), (b), and (c) —H —OCF₃C13(a), (b), and (c) —H —Cl C14(a), (b), and (c) —H —Br C15(a), (b), and(c) —H —I C16(a), (b), and (c) —H -n-butyl C17(a), (b), and (c) —H-n-propyl C18(a), (b), and (c) —Cl —H C19(a), (b), and (c) —Cl-tert-butyl C20(a), (b), and (c) —Cl -iso-butyl C21(a), (b), and (c) —Cl-sec-butyl C22(a), (b), and (c) —Cl -iso-propyl C23(a), (b), and (c) —Cl-n-propyl C24(a), (b), and (c) —Cl -cyclohexyl C25(a), (b), and (c) —Cl-tert-butoxy C26(a), (b), and (c) —Cl -iso-propoxy C27(a), (b), and (c)—Cl —CF₃ C28(a), (b), and (c) —Cl —CH₂CF₃ C29(a), (b), and (c) —Cl —OCF₃C30(a), (b), and (c) —Cl —Cl C31(a), (b), and (c) —Cl —Br C32(a), (b),and (c) —Cl —I C33(a), (b), and (c) —Cl -n-butyl C34(a), (b), and (c)—Cl -n-propyl C35(a), (b), and (c) —F —H C36(a), (b), and (c) —F-tert-butyl C37(a), (b), and (c) —F -iso-butyl C38(a), (b), and (c) —F-sec-butyl C39(a), (b), and (c) —F -iso-propyl C40(a), (b), and (c) —F-n-propyl C41(a), (b), and (c) —F -cyclohexyl C42(a), (b), and (c) —F-tert-butoxy C43(a), (b), and (c) —F -iso-propoxy C44(a), (b), and (c)—F —CF₃ C45(a), (b), and (c) —F —CH₂CF₃ C46(a), (b), and (c) —F —OCF₃C47(a), (b), and (c) —F —Cl C48(a), (b), and (c) —F —Br C49(a), (b), and(c) —F —I C50(a), (b), and (c) —F -n-butyl C51(a), (b), and (c) —F-n-propyl C52(a), (b), and (c) —CH₃ —H C53(a), (b), and (c) —CH₃-iso-butyl C54(a), (b), and (c) —CH₃ -tert-butyl C55(a), (b), and (c)—CH₃ -sec-butyl C56(a), (b), and (c) —CH₃ -iso-propyl C57(a), (b), and(c) —CH₃ -n-propyl C58(a), (b), and (c) —CH₃ -cyclohexyl C59(a), (b),and (c) —CH₃ -tert-butoxy C60(a), (b), and (c) —CH₃ -iso-propoxy C61(a),(b), and (c) —CH₃ —CF₃ C62(a), (b), and (c) —CH₃ —CH₂CF₃ C63(a), (b),and (c) —CH₃ —OCF₃ C64(a), (b), and (c) —CH₃ —Cl C65(a), (b), and (c)—CH₃ —Br C66(a), (b), and (c) —CH₃ —I C67(a), (b), and (c) —CH₃ -n-butylC68(a), (b), and (c) —CH₃ -n-propyl C69(a), (b), and (c) —CF₃ —H C70(a),(b), and (c) —CF₃ -tert-butyl C71(a), (b), and (c) —CF₃ -iso-butylC72(a), (b), and (c) —CF₃ -sec-butyl C73(a), (b), and (c) —CF₃-iso-propyl C74(a), (b), and (c) —CF₃ -n-propyl C75(a), (b), and (c)—CF₃ -cyclohexyl C76(a), (b), and (c) —CF₃ -tert-butoxy C77(a), (b), and(c) —CF₃ -iso-propoxy C78(a), (b), and (c) —CF₃ —CF₃ C79(a), (b), and(c) —CF₃ —CH₂CF₃ C80(a), (b), and (c) —CF₃ —OCF₃ C81(a), (b), and (c)—CF₃ —Cl C82(a), (b), and (c) —CF₃ —Br C83(a), (b), and (c) —CF₃ —IC84(a), (b), and (c) —CF₃ -n-butyl C85(a), (b), and (c) —CF₃ -n-propylC86(a), (b), and (c) —CHF₂ -tert-butyl C87(a), (b), and (c) —CHF₂ —HC88(a), (b), and (c) —CHF₂ -iso-butyl C89(a), (b), and (c) —CHF₂-sec-butyl C90(a), (b), and (c) —CHF₂ -iso-propyl C91(a), (b), and (c)—CHF₂ -n-propyl C92(a), (b), and (c) —CHF₂ -cyclohexyl C93(a), (b), and(c) —CHF₂ -tert-butoxy C94(a), (b), and (c) —CHF₂ -iso-propoxy C95(a),(b), and (c) —CHF₂ —CF₃ C96(a), (b), and (c) —CHF₂ —CH₂CF₃ C97(a), (b),and (c) —CHF₂ —OCF₃ C98(a), (b), and (c) —CHF₂ —Cl C99(a), (b), and (c)—CHF₂ —Br C100(a), (b), and (c) —CHF₂ —I C101(a), (b), and (c) —CHF₂-n-butyl C102(a), (b), and (c) —CHF₂ -n-propyl C103(a), (b), and (c) —OH—H C104(a), (b), and (c) —OH -tert-butyl C105(a), (b), and (c) —OH-iso-butyl C106(a), (b), and (c) —OH -sec-butyl C107(a), (b), and (c)—OH -iso-propyl C108(a), (b), and (c) —OH -n-propyl C109(a), (b), and(c) —OH -cyclohexyl C110(a), (b), and (c) —OH -tert-butoxy C111(a), (b),and (c) —OH -iso-propoxy C112(a), (b), and (c) —OH —CF₃ C113(a), (b),and (c) —OH —CH₂CF₃ C114(a), (b), and (c) —OH —OCF₃ C115(a), (b), and(c) —OH —Cl C116(a), (b), and (c) —OH —Br C117(a), (b), and (c) —OH —IC118(a), (b), and (c) —OH -n-butyl C119(a), (b), and (c) —OH -n-propylC120(a), (b), and (c) —NO₂ —H C121(a), (b), and (c) —NO₂ -tert-butylC122(a), (b), and (c) —NO₂ -iso-butyl C123(a), (b), and (c) —NO₂-sec-butyl C124(a), (b), and (c) —NO₂ -iso-propyl C125(a), (b), and (c)—NO₂ -n-propyl C126(a), (b), and (c) —NO₂ -cyclohexyl C127(a), (b), and(c) —NO₂ -tert-butoxy C128(a), (b), and (c) —NO₂ -iso-propoxy C129(a),(b), and (c) —NO₂ —CF₃ C130(a), (b), and (c) —NO₂ —CH₂CF₃ C131(a), (b),and (c) —NO₂ —OCF₃ C132(a), (b), and (c) —NO₂ —Cl C133(a), (b), and (c)—NO₂ —Br C134(a), (b), and (c) —NO₂ —I C135(a), (b), and (c) —NO₂-n-butyl C136(a), (b), and (c) —NO₂ -n-propyl C137(a), (b), and (c) —CN—H C138(a), (b), and (c) —CN -tert-butyl C139(a), (b), and (c) —CN-iso-butyl C140(a), (b), and (c) —CN -sec-butyl C141(a), (b), and (c)—CN -iso-propyl C142(a), (b), and (c) —CN -n-propyl C143(a), (b), and(c) —CN -cyclohexyl C144(a), (b), and (c) —CN -tert-butoxy C145(a), (b),and (c) —CN -iso-propoxy C146(a), (b), and (c) —CN —CF₃ C147(a), (b),and (c) —CN —CH₂CF₃ C148(a), (b), and (c) —CN —OCF₃ C149(a), (b), and(c) —CN —Cl C150(a), (b), and (c) —CN —Br C151(a), (b), and (c) —CN —IC152(a), (b), and (c) —CN -n-butyl C153(a), (b), and (c) —CN -n-propylC154(a), (b), and (c) —Br —H C155(a), (b), and (c) —Br -tent-butylC156(a), (b), and (c) —Br -iso-butyl C157(a), (b), and (c) —Br-sec-butyl C158(a), (b), and (c) —Br -iso-propyl C159(a), (b), and (c)—Br -n-propyl C160(a), (b), and (c) —Br -cyclohexyl C161(a), (b), and(c) —Br -tert-butoxy C162(a), (b), and (c) —Br -iso-propoxy C163(a),(b), and (c) —Br —CF₃ C164(a), (b), and (c) —Br —CH₂CF₃ C165(a), (b),and (c) —Br —OCF₃ C166(a), (b), and (c) —Br —Cl C167(a), (b), and (c)—Br —Br C168(a), (b), and (c) —Br —I C169(a), (b), and (c) —Br -n-butylC170(a), (b), and (c) —Br -n-propyl C171(a), (b), and (c) —I -tent-butylC172(a), (b), and (c) —I —H C173(a), (b), and (c) —I -iso-butyl C174(a),(b), and (c) —I -sec-butyl C175(a), (b), and (c) —I -iso-propyl C176(a),(b), and (c) —I -n-propyl C177(a), (b), and (c) —I -cyclohexyl C178(a),(b), and (c) —I -tert-butoxy C179(a), (b), and (c) —I -iso-propoxyC180(a), (b), and (c) —I —CF₃ C181(a), (b), and (c) —I —CH₂CF₃ C182(a),(b), and (c) —I —OCF₃ C183(a), (b), and (c) —I —Cl C184(a), (b), and (c)—I —Br C185(a), (b), and (c) —I —I C186(a), (b), and (c) —I -n-butylC187(a), (b), and (c) —I -n-propyl (a) means that R₁₂ is —H and R₁₄ is—CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is —H. (c) means that R₁₂ andR₁₄ are each —H.

TABLE 4 (Id)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₈D01(a), (b), and (c) —H —H D02(a), (b), and (c) —H -tert-butyl D03(a),(b), and (c) —H -iso-butyl D04(a), (b), and (c) —H -sec-butyl D05(a),(b), and (c) —H -iso-propyl D06(a), (b), and (c) —H -n-propyl D07(a),(b), and (c) —H -cyclohexyl D08(a), (b), and (c) —H -tert-butoxy D09(a),(b), and (c) —H -iso-propoxy D10(a), (b), and (c) —H —CF₃ D11(a), (b),and (c) —H —CH₂CF₃ D12(a), (b), and (c) —H —OCF₃ D13(a), (b), and (c) —H—Cl D14(a), (b), and (c) —H —Br D15(a), (b), and (c) —H —I D16(a), (b),and (c) —H -n-butyl D17(a), (b), and (c) —H -n-propyl D18(a), (b), and(c) —Cl —H D19(a), (b), and (c) —Cl -tert-butyl D20(a), (b), and (c) —Cl-iso-butyl D21(a), (b), and (c) —Cl -sec-butyl D22(a), (b), and (c) —Cl-iso-propyl D23(a), (b), and (c) —Cl -n-propyl D24(a), (b), and (c) —Cl-cyclohexyl D25(a), (b), and (c) —Cl -tert-butoxy D26(a), (b), and (c)—Cl -iso-propoxy D27(a), (b), and (c) —Cl —CF₃ D28(a), (b), and (c) —Cl—CH₂CF₃ D29(a), (b), and (c) —Cl —OCF₃ D30(a), (b), and (c) —Cl —ClD31(a), (b), and (c) —Cl —Br D32(a), (b), and (c) —Cl —I D33(a), (b),and (c) —Cl -n-butyl D34(a), (b), and (c) —Cl -n-propyl D35(a), (b), and(c) —F —H D36(a), (b), and (c) —F -tert-butyl D37(a), (b), and (c) —F-iso-butyl D38(a), (b), and (c) —F -sec-butyl D39(a), (b), and (c) —F-iso-propyl D40(a), (b), and (c) —F -n-propyl D41(a), (b), and (c) —F-cyclohexyl D42(a), (b), and (c) —F -tert-butoxy D43(a), (b), and (c) —F-iso-propoxy D44(a), (b), and (c) —F —CF₃ D45(a), (b), and (c) —F—CH₂CF₃ D46(a), (b), and (c) —F —OCF₃ D47(a), (b), and (c) —F —ClD48(a), (b), and (c) —F —Br D49(a), (b), and (c) —F —I D50(a), (b), and(c) —F -n-butyl D51(a), (b), and (c) —F -n-propyl D52(a), (b), and (c)—CH₃ —H D53(a), (b), and (c) —CH₃ -tert-butyl D54(a), (b), and (c) —CH₃-iso-butyl D55(a), (b), and (c) —CH₃ -sec-butyl D56(a), (b), and (c)—CH₃ -iso-propyl D57(a), (b), and (c) —CH₃ -n-propyl D58(a), (b), and(c) —CH₃ -cyclohexyl D59(a), (b), and (c) —CH₃ -tert-butoxy D60(a), (b),and (c) —CH₃ -iso-propoxy D61(a), (b), and (c) —CH₃ —CF₃ D62(a), (b),and (c) —CH₃ —CH₂CF₃ D63(a), (b), and (c) —CH₃ —OCF₃ D64(a), (b), and(c) —CH₃ —Cl D65(a), (b), and (c) —CH₃ —Br D66(a), (b), and (c) —CH₃ —ID67(a), (b), and (c) —CH₃ -n-butyl D68(a), (b), and (c) —CH₃ -n-propylD69(a), (b), and (c) —CF₃ —H D70(a), (b), and (c) —CF₃ -tert-butylD71(a), (b), and (c) —CF₃ -iso-butyl D72(a), (b), and (c) —CF₃-sec-butyl D73(a), (b), and (c) —CF₃ -iso-propyl D74(a), (b), and (c)—CF₃ -n-propyl D75(a), (b), and (c) —CF₃ -cyclohexyl D76(a), (b), and(c) —CF₃ -tert-butoxy D77(a), (b), and (c) —CF₃ -iso-propoxy D78(a),(b), and (c) —CF₃ —CF₃ D79(a), (b), and (c) —CF₃ —CH₂CF₃ D80(a), (b),and (c) —CF₃ —OCF₃ D81(a), (b), and (c) —CF₃ —Cl D82(a), (b), and (c)—CF₃ —Br D83(a), (b), and (c) —CF₃ —I D84(a), (b), and (c) —CF₃ -n-butylD85(a), (b), and (c) —CF₃ -n-propyl D86(a), (b), and (c) —CHF₂-tert-butyl D87(a), (b), and (c) —CHF₂ —H D88(a), (b), and (c) —CHF₂-iso-butyl D89(a), (b), and (c) —CHF₂ -sec-butyl D90(a), (b), and (c)—CHF₂ -iso-propyl D91(a), (b), and (c) —CHF₂ -n-propyl D92(a), (b), and(c) —CHF₂ -cyclohexyl D93(a), (b), and (c) —CHF₂ -tert-butoxy D94(a),(b), and (c) —CHF₂ -iso-propoxy D95(a), (b), and (c) —CHF₂ —CF₃ D96(a),(b), and (c) —CHF₂ —CH₂CF₃ D97(a), (b), and (c) —CHF₂ —OCF₃ D98(a), (b),and (c) —CHF₂ —Cl D99(a), (b), and (c) —CHF₂ —Br D100(a), (b), and (c)—CHF₂ —I D101(a), (b), and (c) —CHF₂ -n-butyl D102(a), (b), and (c)—CHF₂ -n-propyl D103(a), (b), and (c) —OH —H D104(a), (b), and (c) —OH-tert-butyl D105(a), (b), and (c) —OH -iso-butyl D106(a), (b), and (c)—OH -sec-butyl D107(a), (b), and (c) —OH -iso-propyl D108(a), (b), and(c) —OH -n-propyl D109(a), (b), and (c) —OH -cyclohexyl D110(a), (b),and (c) —OH -tert-butoxy D111(a), (b), and (c) —OH -iso-propoxy D112(a),(b), and (c) —OH —CF₃ D113(a), (b), and (c) —OH —CH₂CF₃ D114(a), (b),and (c) —OH —OCF₃ D115(a), (b), and (c) —OH —Cl D116(a), (b), and (c)—OH —Br D117(a), (b), and (c) —OH —I D118(a), (b), and (c) —OH -n-butylD119(a), (b), and (c) —OH -n-propyl D120(a), (b), and (c) —NO₂ —HD121(a), (b), and (c) —NO₂ -tert-butyl D122(a), (b), and (c) —NO₂-iso-butyl D123(a), (b), and (c) —NO₂ -sec-butyl D124(a), (b), and (c)—NO₂ -iso-propyl D125(a), (b), and (c) —NO₂ -n-propyl D126(a), (b), and(c) —NO₂ -cyclohexyl D127(a), (b), and (c) —NO₂ -tert-butoxy D128(a),(b), and (c) —NO₂ -iso-propoxy D129(a), (b), and (c) —NO₂ —CF₃ D130(a),(b), and (c) —NO₂ —CH₂CF₃ D131(a), (b), and (c) —NO₂ —OCF₃ D132(a), (b),and (c) —NO₂ —Cl D133(a), (b), and (c) —NO₂ —Br D134(a), (b), and (c)—NO₂ —I D135(a), (b), and (c) —NO₂ -n-butyl D136(a), (b), and (c) —NO₂-n-propyl D137(a), (b), and (c) —CN —H D138(a), (b), and (c) —CN-tert-butyl D139(a), (b), and (c) —CN -iso-butyl D140(a), (b), and (c)—CN -sec-butyl D141(a), (b), and (c) —CN -iso-propyl D142(a), (b), and(c) —CN -n-propyl D143(a), (b), and (c) —CN -cyclohexyl D144(a), (b),and (c) —CN -tert-butoxy D145(a), (b), and (c) —CN -iso-propoxy D146(a),(b), and (c) —CN —CF₃ D147(a), (b), and (c) —CN —CH₂CF₃ D148(a), (b),and (c) —CN —OCF₃ D149(a), (b), and (c) —CN —Cl D150(a), (b), and (c)—CN —Br D151(a), (b), and (c) —CN —I D152(a), (b), and (c) —CN -n-butylD153(a), (b), and (c) —CN -n-propyl D154(a), (b), and (c) —Br —HD155(a), (b), and (c) —Br -tert-butyl D156(a), (b), and (c) —Br-iso-butyl D157(a), (b), and (c) —Br -sec-butyl D158(a), (b), and (c)—Br -iso-propyl D159(a), (b), and (c) —Br -n-propyl D160(a), (b), and(c) —Br -cyclohexyl D161(a), (b), and (c) —Br -tert-butoxy D162(a), (b),and (c) —Br -iso-propoxy D163(a), (b), and (c) —Br —CF₃ D164(a), (b),and (c) —Br —CH₂CF₃ D165(a), (b), and (c) —Br —OCF₃ D166(a), (b), and(c) —Br —Cl D167(a), (b), and (c) —Br —Br D168(a), (b), and (c) —Br —ID169(a), (b), and (c) —Br -n-butyl D170(a), (b), and (c) —Br -n-propylD171(a), (b), and (c) —I -tert-butyl D172(a), (b), and (c) —I —HD173(a), (b), and (c) —I -iso-butyl D174(a), (b), and (c) —I -sec-butylD175(a), (b), and (c) —I -iso-propyl D176(a), (b), and (c) —I -n-propylD177(a), (b), and (c) —I -cyclohexyl D178(a), (b), and (c) —I-tert-butoxy D179(a), (b), and (c) —I -iso-propoxy D180(a), (b), and (c)—I —CF₃ D181(a), (b), and (c) —I —CH₂CF₃ D182(a), (b), and (c) —I —OCF₃D183(a), (b), and (c) —I —Cl D184(a), (b), and (c) —I —Br D185(a), (b),and (c) —I —I D186(a), (b), and (c) —I -n-butyl D187(a), (b), and (c) —I-n-propyl (a) means that R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂is —CH₃ and R₁₄ is —H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 5 (Ie)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁(R₈)_(a) (R₈)_(b) E01(a), (b), and (c) S —H —Cl —H E02(a), (b), and (c)S —H —Br —H E03(a), (b), and (c) S —H —F —H E04(a), (b), and (c) S —H—CH₃ —H E05(a), (b), and (c) S —H —CF₃ —H E06(a), (b), and (c) S —H—OCH₃ —H E07(a), (b), and (c) S —H —OCH₂CH₃ —H E08(a), (b), and (c) S —H—OCF₃ —H E09(a), (b), and (c) S —H -tert-butyl —H E10(a), (b), and (c) S—H -iso-propyl —H E11(a), (b), and (c) S —H —CH₃ —CH₃ E12(a), (b), and(c) S —H —H —H E13(a), (b), and (c) S —H —H —Cl E14(a), (b), and (c) S—H —H —Br E15(a), (b), and (c) S —H —H —F E16(a), (b), and (c) S —H —H—CH₃ E17(a), (b), and (c) S —H —H —CF₃ E18(a), (b), and (c) S —H —H—OCH₃ E19(a), (b), and (c) S —H —H —OCH₂CH₃ E20(a), (b), and (c) S —H —H—OCF₃ E21(a), (b), and (c) S —H —H -tert-butyl E22(a), (b), and (c) S —H—H -iso-propyl E23(a), (b), and (c) S —Cl —Cl —H E24(a), (b), and (c) S—Cl —Br —H E25(a), (b), and (c) S —Cl —F —H E26(a), (b), and (c) S —Cl—CH₃ —H E27(a), (b), and (c) S —Cl —CF₃ —H E28(a), (b), and (c) S —Cl—OCH₃ —H E29(a), (b), and (c) S —Cl —OCH₂CH₃ —H E30(a), (b), and (c) S—Cl —OCF₃ —H E31(a), (b), and (c) S —Cl -tert-butyl —H E32(a), (b), and(c) S —Cl -iso-propyl —H E33(a), (b), and (c) S —Cl —CH₃ —CH₃ E34(a),(b), and (c) S —Cl —H —H E35(a), (b), and (c) S —Cl —H —Cl E36(a), (b),and (c) S —Cl —H —Br E37(a), (b), and (c) S —Cl —H —F E38(a), (b), and(c) S —Cl —H —CH₃ E39(a), (b), and (c) S —Cl —H —CF₃ E40(a), (b), and(c) S —Cl —H —OCH₃ E41(a), (b), and (c) S —Cl —H —OCH₂CH₃ E42(a), (b),and (c) S —Cl —H —OCF₃ E43(a), (b), and (c) S —Cl —H -tert-butyl E44(a),(b), and (c) S —Cl —H -iso-propyl E45(a), (b), and (c) S —Cl —H —OCF₃E46(a), (b), and (c) S —Cl —H -tert-butyl E47(a), (b), and (c) S —Cl —H-iso-propyl E48(a), (b), and (c) S —CH₃ —Cl —H E49(a), (b), and (c) S—CH₃ —Br —H E50(a), (b), and (c) S —CH₃ —F —H E51(a), (b), and (c) S—CH₃ —CH₃ —H E52(a), (b), and (c) S —CH₃ —CF₃ —H E53(a), (b), and (c) S—CH₃ —OCH₃ —H E54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H E55(a), (b), and(c) S —CH₃ —OCF₃ —H E56(a), (b), and (c) S —CH₃ -tert-butyl —H E57(a),(b), and (c) S —CH₃ -iso-propyl —H E58(a), (b), and (c) S —CH₃ —CH₃ —CH₃E59(a), (b), and (c) S —CH₃ —H —H E60(a), (b), and (c) S —CH₃ —H —ClE61(a), (b), and (c) S —CH₃ —H —Br E62(a), (b), and (c) S —CH₃ —H —FE63(a), (b), and (c) S —CH₃ —H —CH₃ E64(a), (b), and (c) S —CH₃ —H —CF₃E65(a), (b), and (c) S —CH₃ —H —OCH₃ E66(a), (b), and (c) S —CH₃ —H—OCH₂CH₃ E67(a), (b), and (c) S —CH₃ —H —OCF₃ E68(a), (b), and (c) S—CH₃ —H -tert-butyl E69(a), (b), and (c) S —CH₃ —H -iso-propyl E70(a),(b), and (c) S —CF₃ —Cl —H E71(a), (b), and (c) S —CF₃ —Br —H E72(a),(b), and (c) S —CF₃ —F —H E73(a), (b), and (c) S —CF₃ —CH₃ —H E74(a),(b), and (c) S —CF₃ —CF₃ —H E75(a), (b), and (c) S —CF₃ —OCH₃ —H E76(a),(b), and (c) S —CF₃ —OCH₂CH₃ —H E77(a), (b), and (c) S —CF₃ —OCF₃ —HE78(a), (b), and (c) S —CF₃ -tert-butyl —H E79(a), (b), and (c) S —CF₃-iso-propyl —H E80(a), (b), and (c) S —CF₃ —CH₃ —CH₃ E81(a), (b), and(c) S —CF₃ —H —H E82(a), (b), and (c) S —CF₃ —H —Cl E83(a), (b), and (c)S —CF₃ —H —Br E84(a), (b), and (c) S —CF₃ —H —F E85(a), (b), and (c) S—CF₃ —H —CH₃ E86(a), (b), and (c) S —CF₃ —H —CF₃ E87(a), (b), and (c) S—CF₃ —H —OCH₃ E88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ E89(a), (b), and(c) S —CF₃ —H —OCF₃ E90(a), (b), and (c) S —CF₃ —H -tert-butyl E91(a),(b), and (c) S —CF₃ —H -iso-propyl E92(a), (b), and (c) S —CHF₂ —Cl —HE93(a), (b), and (c) S —CHF₂ —Br —H E94(a), (b), and (c) S —CHF₂ —F —HE95(a), (b), and (c) S —CHF₂ —CH₃ —H E96(a), (b), and (c) S —CHF₂ —CF₃—H E97(a), (b), and (c) S —CHF₂ —OCH₃ —H E98(a), (b), and (c) S —CHF₂—OCH₂CH₃ —H E99(a), (b), and (c) S —CHF₂ —OCF₃ —H E100(a), (b), and (c)S —CHF₂ -tert-butyl —H E101(a), (b), and (c) S —CHF₂ -iso-propyl —HE102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ E103(a), (b), and (c) S —CHF₂ —H—H E104(a), (b), and (c) S —CHF₂ —H —Cl E105(a), (b), and (c) S —CHF₂ —H—Br E106(a), (b), and (c) S —CHF₂ —H —F E107(a), (b), and (c) S —CHF₂ —H—CH₃ E108(a), (b), and (c) S —CHF₂ —H —CF₃ E109(a), (b), and (c) S —CHF₂—H —OCH₃ E110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ E111(a), (b), and (c)S —CHF₂ —H —OCF₃ E112(a), (b), and (c) S —CHF₂ —H -tert-butyl E113(a),(b), and (c) S —CHF₂ —H -iso-propyl E114(a), (b), and (c) S —OH —Cl —HE115(a), (b), and (c) S —OH —Br —H E116(a), (b), and (c) S —OH —F —HE117(a), (b), and (c) S —OH —CH₃ —H E118(a), (b), and (c) S —OH —CF₃ —HE119(a), (b), and (c) S —OH —OCH₃ —H E120(a), (b), and (c) S —OH—OCH₂CH₃ —H E121(a), (b), and (c) S —OH —OCF₃ —H E122(a), (b), and (c) S—OH -tert-butyl —H E123(a), (b), and (c) S —OH -iso-propyl —H E124(a),(b), and (c) S —OH —CH₃ —CH₃ E125(a), (b), and (c) S —OH —H —H E126(a),(b), and (c) S —OH —H —Cl E127(a), (b), and (c) S —OH —H —Br E128(a),(b), and (c) S —OH —H —F E129(a), (b), and (c) S —OH —H —CH₃ E130(a),(b), and (c) S —OH —H —CF₃ E131(a), (b), and (c) S —OH —H —OCH₃ E132(a),(b), and (c) S —OH —H —OCH₂CH₃ E133(a), (b), and (c) S —OH —H —OCF₃E134(a), (b), and (c) S —OH —H -tert-butyl E135(a), (b), and (c) S —OH—H -iso-propyl E136(a), (b), and (c) S —NO₂ —Cl —H E137(a), (b), and (c)S —NO₂ —Br —H E138(a), (b), and (c) S —NO₂ —F —H E139(a), (b), and (c) S—NO₂ —CH₃ —H E140(a), (b), and (c) S —NO₂ —CF₃ —H E141(a), (b), and (c)S —NO₂ —OCH₃ —H E142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H E143(a), (b),and (c) S —NO₂ —OCF₃ —H E144(a), (b), and (c) S —NO₂ -tert-butyl —HE145(a), (b), and (c) S —NO₂ -iso-propyl —H E146(a), (b), and (c) S —NO₂—CH₃ —CH₃ E147(a), (b), and (c) S —NO₂ —H —H E148(a), (b), and (c) S—NO₂ —H —Cl E149(a), (b), and (c) S —NO₂ —H —Br E150(a), (b), and (c) S—NO₂ —H —F E151(a), (b), and (c) S —NO₂ —H —CH₃ E152(a), (b), and (c) S—NO₂ —H —CF₃ E153(a), (b), and (c) S —NO₂ —H —OCH₃ E154(a), (b), and (c)S —NO₂ —H —OCH₂CH₃ E155(a), (b), and (c) S —NO₂ —H —OCF₃ E156(a), (b),and (c) S —NO₂ —H -tert-butyl E157(a), (b), and (c) S —NO₂ —H-iso-propyl E158(a), (b), and (c) S —CN —Br —H E159(a), (b), and (c) S—CN —Cl —H E160(a), (b), and (c) S —CN —F —H E161(a), (b), and (c) S —CN—CH₃ —H E162(a), (b), and (c) S —CN —CF₃ —H E163(a), (b), and (c) S —CN—OCH₃ —H E164(a), (b), and (c) S —CN —OCH₂CH₃ —H E165(a), (b), and (c) S—CN —OCF₃ —H E166(a), (b), and (c) S —CN -tert-butyl —H E167(a), (b),and (c) S —CN -iso-propyl —H E168(a), (b), and (c) S —CN —CH₃ —CH₃E169(a), (b), and (c) S —CN —H —H E170(a), (b), and (c) S —CN —H —ClE171(a), (b), and (c) S —CN —H —Br E172(a), (b), and (c) S —CN —H —FE173(a), (b), and (c) S —CN —H —CH₃ E174(a), (b), and (c) S —CN —H —CF₃E175(a), (b), and (c) S —CN —H —OCH₃ E176(a), (b), and (c) S —CN —H—OCH₂CH₃ E177(a), (b), and (c) S —CN —H —OCF₃ E178(a), (b), and (c) S—CN —H -tert-butyl E179(a), (b), and (c) S —CN —H -iso-propyl E180(a),(b), and (c) S —Br —Br —H E181(a), (b), and (c) S —Br —Cl —H E182(a),(b), and (c) S —Br —F —H E183(a), (b), and (c) S —Br —CH₃ —H E184(a),(b), and (c) S —Br —CF₃ —H E185(a), (b), and (c) S —Br —OCH₃ —H E186(a),(b), and (c) S —Br —OCH₂CH₃ —H E187(a), (b), and (c) S —Br —OCF₃ —HE188(a), (b), and (c) S —Br -tert-butyl —H E189(a), (b), and (c) S —Br-iso-propyl —H E190(a), (b), and (c) S —Br —CH₃ —CH₃ E191(a), (b), and(c) S —Br —H —H E192(a), (b), and (c) S —Br —H —Cl E193(a), (b), and (c)S —Br —H —Br E194(a), (b), and (c) S —Br —H —F E195(a), (b), and (c) S—Br —H —CH₃ E196(a), (b), and (c) S —Br —H —CF₃ E197(a), (b), and (c) S—Br —H —OCH₃ E198(a), (b), and (c) S —Br —H —OCH₂CH₃ E199(a), (b), and(c) S —Br —H —OCF₃ E200(a), (b), and (c) S —Br —H -tert-butyl E201(a),(b), and (c) S —Br —H -iso-propyl E202(a), (b), and (c) S —I —Cl —HE203(a), (b), and (c) S —I —Br —H E204(a), (b), and (c) S —I —F —HE205(a), (b), and (c) S —I —CH₃ —H E206(a), (b), and (c) S —I —CF₃ —HE207(a), (b), and (c) S —I —OCH₃ —H E208(a), (b), and (c) S —I —OCH₂CH₃—H E209(a), (b), and (c) S —I —OCF₃ —H E210(a), (b), and (c) S —I-tert-butyl —H E211(a), (b), and (c) S —I -iso-propyl —H E212(a), (b),and (c) S —I —CH₃ —CH₃ E213(a), (b), and (c) S —I —H —H E214(a), (b),and (c) S —I —H —Cl E215(a), (b), and (c) S —I —H —Br E216(a), (b), and(c) S —I —H —F E217(a), (b), and (c) S —I —H —CH₃ E218(a), (b), and (c)S —I —H —CF₃ E219(a), (b), and (c) S —I —H —OCH₃ E220(a), (b), and (c) S—I —H —OCH₂CH₃ E221(a), (b), and (c) S —I —H —OCF₃ E222(a), (b), and (c)S —I —H -tert-butyl E223(a), (b), and (c) S —I —H -iso-propyl E224(a),(b), and (c) O —H —Cl —H E225(a), (b), and (c) O —H —Br —H E226(a), (b),and (c) O —H —F —H E227(a), (b), and (c) O —H —CH₃ —H E228(a), (b), and(c) O —H —CF₃ —H E229(a), (b), and (c) O —H —OCH₃ —H E230(a), (b), and(c) O —H —OCH₂CH₃ —H E231(a), (b), and (c) O —H —OCF₃ —H E232(a), (b),and (c) O —H -tert-butyl —H E233(a), (b), and (c) O —H -iso-propyl —HE234(a), (b), and (c) O —H —CH₃ —CH₃ E235(a), (b), and (c) O —H —H —HE236(a), (b), and (c) O —H —H —Cl E237(a), (b), and (c) O —H —H —BrE238(a), (b), and (c) O —H —H —F E239(a), (b), and (c) O —H —H —CH₃E240(a), (b), and (c) O —H —H —CF₃ E241(a), (b), and (c) O —H —H —OCH₃E242(a), (b), and (c) O —H —H —OCH₂CH₃ E243(a), (b), and (c) O —H —H—OCF₃ E244(a), (b), and (c) O —H —H -tert-butyl E245(a), (b), and (c) O—H —H -iso-propyl E246(a), (b), and (c) O —Cl —Cl —H E247(a), (b), and(c) O —Cl —Br —H E248(a), (b), and (c) O —Cl —F —H E249(a), (b), and (c)O —Cl —CH₃ —H E250(a), (b), and (c) O —Cl —CF₃ —H E251(a), (b), and (c)O —Cl —OCH₃ —H E252(a), (b), and (c) O —Cl —OCH₂CH₃ —H E253(a), (b), and(c) O —Cl —OCF₃ —H E254(a), (b), and (c) O —Cl -tert-butyl —H E255(a),(b), and (c) O —Cl -iso-propyl —H E256(a), (b), and (c) O —Cl —CH₃ —CH₃E257(a), (b), and (c) O —Cl —H —H E258(a), (b), and (c) O —Cl —H —CH₃E259(a), (b), and (c) O —Cl —H —Cl E260(a), (b), and (c) O —Cl —H —BrE261(a), (b), and (c) O —Cl —H —F E262(a), (b), and (c) O —Cl —H —CF₃E263(a), (b), and (c) O —Cl —H —OCH₃ E264(a), (b), and (c) O —Cl —H—OCH₂CH₃ E265(a), (b), and (c) O —Cl —H —OCF₃ E266(a), (b), and (c) O—Cl —H -tert-butyl E267(a), (b), and (c) O —Cl —H -iso-propyl E268(a),(b), and (c) O —Cl —H —OCF₃ E269(a), (b), and (c) O —Cl —H -tert-butylE270(a), (b), and (c) O —Cl —H -iso-propyl E271(a), (b), and (c) O —CH₃—Cl —H E272(a), (b), and (c) O —CH₃ —Br —H E273(a), (b), and (c) O —CH₃—F —H E274(a), (b), and (c) O —CH₃ —CH₃ —H E275(a), (b), and (c) O —CH₃—CF₃ —H E276(a), (b), and (c) O —CH₃ —OCH₃ —H E277(a), (b), and (c) O—CH₃ —OCH₂CH₃ —H E278(a), (b), and (c) O —CH₃ —OCF₃ —H E279(a), (b), and(c) O —CH₃ -tert-butyl —H E280(a), (b), and (c) O —CH₃ -iso-propyl —HE281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ E282(a), (b), and (c) O —CH₃ —H—H E283(a), (b), and (c) O —CH₃ —H —Cl E284(a), (b), and (c) O —CH₃ —H—Br E285(a), (b), and (c) O —CH₃ —H —F E286(a), (b), and (c) O —CH₃ —H—CH₃ E287(a), (b), and (c) O —CH₃ —H —CF₃ E288(a), (b), and (c) O —CH₃—H —OCH₃ E289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ E290(a), (b), and (c)O —CH₃ —H —OCF₃ E291(a), (b), and (c) O —CH₃ —H -tert-butyl E292(a),(b), and (c) O —CH₃ —H -iso-propyl E293(a), (b), and (c) O —CF₃ —Cl —HE294(a), (b), and (c) O —CF₃ —Br —H E295(a), (b), and (c) O —CF₃ —F —HE296(a), (b), and (c) O —CF₃ —CH₃ —H E297(a), (b), and (c) O —CF₃ —CF₃—H E298(a), (b), and (c) O —CF₃ —OCH₃ —H E299(a), (b), and (c) O —CF₃—OCH₂CH₃ —H E300(a), (b), and (c) O —CF₃ —OCF₃ —H E301(a), (b), and (c)O —CF₃ -tert-butyl —H E302(a), (b), and (c) O —CF₃ -iso-propyl —HE303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ E304(a), (b), and (c) O —CF₃ —H—H E305(a), (b), and (c) O —CF₃ —H —Cl E306(a), (b), and (c) O —CF₃ —H—Br E307(a), (b), and (c) O —CF₃ —H —F E308(a), (b), and (c) O —CF₃ —H—CH₃ E309(a), (b), and (c) O —CF₃ —H —CF₃ E310(a), (b), and (c) O —CF₃—H —OCH₃ E311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ E312(a), (b), and (c)O —CF₃ —H —OCF₃ E313(a), (b), and (c) O —CF₃ —H -tert-butyl E314(a),(b), and (c) O —CF₃ —H -iso-propyl E315(a), (b), and (c) O —CHF₂ —Cl —HE316(a), (b), and (c) O —CHF₂ —Br —H E317(a), (b), and (c) O —CHF₂ —F —HE318(a), (b), and (c) O —CHF₂ —CH₃ —H E319(a), (b), and (c) O —CHF₂ —CF₃—H E320(a), (b), and (c) O —CHF₂ —OCH₃ —H E321(a), (b), and (c) O —CHF₂—OCH₂CH₃ —H E322(a), (b), and (c) O —CHF₂ —OCF₃ —H E323(a), (b), and (c)O —CHF₂ -tert-butyl —H E324(a), (b), and (c) O —CHF₂ -iso-propyl —HE325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ E326(a), (b), and (c) O —CHF₂ —H—H E327(a), (b), and (c) O —CHF₂ —H —Cl E328(a), (b), and (c) O —CHF₂ —H—Br E329(a), (b), and (c) O —CHF₂ —H —F E330(a), (b), and (c) O —CHF₂ —H—CH₃ E331(a), (b), and (c) O —CHF₂ —H —CF₃ E332(a), (b), and (c) O —CHF₂—H —OCH₃ E333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ E334(a), (b), and (c)O —CHF₂ —H —OCF₃ E335(a), (b), and (c) O —CHF₂ —H -tert-butyl E336(a),(b), and (c) O —CHF₂ —H -iso-propyl E337(a), (b), and (c) O —OH —Cl —HE338(a), (b), and (c) O —OH —Br —H E339(a), (b), and (c) O —OH —F —HE340(a), (b), and (c) O —OH —CH₃ —H E341(a), (b), and (c) O —OH —CF₃ —HE342(a), (b), and (c) O —OH —OCH₃ —H E343(a), (b), and (c) O —OH—OCH₂CH₃ —H E344(a), (b), and (c) O —OH —OCF₃ —H E345(a), (b), and (c) O—OH -tert-butyl —H E346(a), (b), and (c) O —OH -iso-propyl —H E347(a),(b), and (c) O —OH —CH₃ —CH₃ E348(a), (b), and (c) O —OH —H —H E349(a),(b), and (c) O —OH —H —Cl E350(a), (b), and (c) O —OH —H —Br E351(a),(b), and (c) O —OH —H —F E352(a), (b), and (c) O —OH —H —CH₃ E353(a),(b), and (c) O —OH —H —CF₃ E354(a), (b), and (c) O —OH —H —OCH₃ E355(a),(b), and (c) O —OH —H —OCH₂CH₃ E356(a), (b), and (c) O —OH —H —OCF₃E357(a), (b), and (c) O —OH —H -tert-butyl E358(a), (b), and (c) O —OH—H -iso-propyl E359(a), (b), and (c) O —NO₂ —Cl —H E360(a), (b), and (c)O —NO₂ —Br —H E361(a), (b), and (c) O —NO₂ —F —H E362(a), (b), and (c) O—NO₂ —CH₃ —H E363(a), (b), and (c) O —NO₂ —CF₃ —H E364(a), (b), and (c)O —NO₂ —OCH₃ —H E365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H E366(a), (b),and (c) O —NO₂ —OCF₃ —H E367(a), (b), and (c) O —NO₂ -tert-butyl —HE368(a), (b), and (c) O —NO₂ -iso-propyl —H E369(a), (b), and (c) O —NO₂—CH₃ —CH₃ E370(a), (b), and (c) O —NO₂ —H —H E371(a), (b), and (c) O—NO₂ —H —Cl E372(a), (b), and (c) O —NO₂ —H —Br E373(a), (b), and (c) O—NO₂ —H —F E374(a), (b), and (c) O —NO₂ —H —CH₃ E375(a), (b), and (c) O—NO₂ —H —CF₃ E376(a), (b), and (c) O —NO₂ —H —OCH₃ E377(a), (b), and (c)O —NO₂ —H —OCH₂CH₃ E378(a), (b), and (c) O —NO₂ —H —OCF₃ E379(a), (b),and (c) O —NO₂ —H -tert-butyl E380(a), (b), and (c) O —NO₂ —H-iso-propyl E381(a), (b), and (c) O —CN —Br —H E382(a), (b), and (c) O—CN —Cl —H E383(a), (b), and (c) O —CN —F —H E384(a), (b), and (c) O —CN—CH₃ —H E385(a), (b), and (c) O —CN —CF₃ —H E386(a), (b), and (c) O —CN—OCH₃ —H E387(a), (b), and (c) O —CN —OCH₂CH₃ —H E388(a), (b), and (c) O—CN —OCF₃ —H E389(a), (b), and (c) O —CN -tert-butyl —H E390(a), (b),and (c) O —CN -iso-propyl —H E391(a), (b), and (c) O —CN —CH₃ —CH₃E392(a), (b), and (c) O —CN —H —H E393(a), (b), and (c) O —CN —H —ClE394(a), (b), and (c) O —CN —H —Br E395(a), (b), and (c) O —CN —H —FE396(a), (b), and (c) O —CN —H —CH₃ E397(a), (b), and (c) O —CN —H —CF₃E398(a), (b), and (c) O —CN —H —OCH₃ E399(a), (b), and (c) O —CN —H—OCH₂CH₃ E400(a), (b), and (c) O —CN —H —OCF₃ E401(a), (b), and (c) O—CN —H -tert-butyl E402(a), (b), and (c) O —CN —H -iso-propyl E403(a),(b), and (c) O —Br —Br —H E404(a), (b), and (c) O —Br —Cl —H E405(a),(b), and (c) O —Br —F —H E406(a), (b), and (c) O —Br —CH₃ —H E407(a),(b), and (c) O —Br —CF₃ —H E408(a), (b), and (c) O —Br —OCH₃ —H E409(a),(b), and (c) O —Br —OCH₂CH₃ —H E410(a), (b), and (c) O —Br —OCF₃ —HE411(a), (b), and (c) O —Br -tert-butyl —H E412(a), (b), and (c) O —Br-iso-propyl —H E413(a), (b), and (c) O —Br —CH₃ —CH₃ E414(a), (b), and(c) O —Br —H —H E415(a), (b), and (c) O —Br —H —Cl E416(a), (b), and (c)O —Br —H —Br E417(a), (b), and (c) O —Br —H —F E418(a), (b), and (c) O—Br —H —CH₃ E419(a), (b), and (c) O —Br —H —CF₃ E420(a), (b), and (c) O—Br —H —OCH₃ E421(a), (b), and (c) O —Br —H —OCH₂CH₃ E422(a), (b), and(c) O —Br —H —OCF₃ E423(a), (b), and (c) O —Br —H -tert-butyl E424(a),(b), and (c) O —Br —H -iso-propyl E425(a), (b), and (c) O —I —Br —HE426(a), (b), and (c) O —I —Cl —H E427(a), (b), and (c) O —I —F —HE428(a), (b), and (c) O —I —CH₃ —H E429(a), (b), and (c) O —I —CF₃ —HE430(a), (b), and (c) O —I —OCH₃ —H E431(a), (b), and (c) O —I —OCH₂CH₃—H E432(a), (b), and (c) O —I —OCF₃ —H E433(a), (b), and (c) O —I-tert-butyl —H E434(a), (b), and (c) O —I -iso-propyl —H E435(a), (b),and (c) O —I —CH₃ —CH₃ E436(a), (b), and (c) O —I —H —H E437(a), (b),and (c) O —I —H —Cl E438(a), (b), and (c) O —I —H —Br E439(a), (b), and(c) O —I —H —F E440(a), (b), and (c) O —I —H —CH₃ E441(a), (b), and (c)O —I —H —CF₃ E442(a), (b), and (c) O —I —H —OCH₃ E443(a), (b), and (c) O—I —H —OCH₂CH₃ E444(a), (b), and (c) O —I —H —OCF₃ E445(a), (b), and (c)O —I —H -tert-butyl E446(a), (b), and (c) O —I —H -iso-propyl E447(a),(b), and (c) NH —H —Cl —H E448(a), (b), and (c) NH —H —Br —H E449(a),(b), and (c) NH —H —F —H E450(a), (b), and (c) NH —H —CH₃ —H E451(a),(b), and (c) NH —H —CF₃ —H E452(a), (b), and (c) NH —H —OCH₃ —H E453(a),(b), and (c) NH —H —OCH₂CH₃ —H E454(a), (b), and (c) NH —H —OCF₃ —HE455(a), (b), and (c) NH —H -tert-butyl —H E456(a), (b), and (c) NH —H-iso-propyl —H E457(a), (b), and (c) NH —H —CH₃ —CH₃ E458(a), (b), and(c) NH —H —H —H E459(a), (b), and (c) NH —H —H —Cl E460(a), (b), and (c)NH —H —H —Br E461(a), (b), and (c) NH —H —H —F E462(a), (b), and (c) NH—H —H —CH₃ E463(a), (b), and (c) NH —H —H —CF₃ E464(a), (b), and (c) NH—H —H —OCH₃ E465(a), (b), and (c) NH —H —H —OCH₂CH₃ E466(a), (b), and(c) NH —H —H —OCF₃ E467(a), (b), and (c) NH —H —H -tert-butyl E468(a),(b), and (c) NH —H —H -iso-propyl E469(a), (b), and (c) NH —Cl —Cl —HE470(a), (b), and (c) NH —Cl —Br —H E471(a), (b), and (c) NH —Cl —F —HE472(a), (b), and (c) NH —Cl —CH₃ —H E473(a), (b), and (c) NH —Cl —CF₃—H E474(a), (b), and (c) NH —Cl —OCH₃ —H E475(a), (b), and (c) NH —Cl—OCH₂CH₃ —H E476(a), (b), and (c) NH —Cl —OCF₃ —H E477(a), (b), and (c)NH —Cl -tert-butyl —H E478(a), (b), and (c) NH —Cl -iso-propyl —HE479(a), (b), and (c) NH —Cl —CH₃ —CH₃ E480(a), (b), and (c) NH —Cl —H—H E481(a), (b), and (c) NH —Cl —H —CH₃ E482(a), (b), and (c) NH —Cl —H—Cl E483(a), (b), and (c) NH —Cl —H —Br E484(a), (b), and (c) NH —Cl —H—F E485(a), (b), and (c) NH —Cl —H —CF₃ E486(a), (b), and (c) NH —Cl —H—OCH₃ E487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ E488(a), (b), and (c) NH—Cl —H —OCF₃ E489(a), (b), and (c) NH —Cl —H -tert-butyl E490(a), (b),and (c) NH —Cl —H -iso-propyl E491(a), (b), and (c) NH —Cl —H —OCF₃E492(a), (b), and (c) NH —Cl —H -tert-butyl E493(a), (b), and (c) NH —Cl—H -iso-propyl E494(a), (b), and (c) NH —CH₃ —Cl —H E495(a), (b), and(c) NH —CH₃ —Br —H E496(a), (b), and (c) NH —CH₃ —F —H E497(a), (b), and(c) NH —CH₃ —CH₃ —H E498(a), (b), and (c) NH —CH₃ —CF₃ —H E499(a), (b),and (c) NH —CH₃ —OCH₃ —H E500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —HE501(a), (b), and (c) NH —CH₃ —OCF₃ —H E502(a), (b), and (c) NH —CH₃-tert-butyl —H E503(a), (b), and (c) NH —CH₃ -iso-propyl —H E504(a),(b), and (c) NH —CH₃ —CH₃ —CH₃ E505(a), (b), and (c) NH —CH₃ —H —HE506(a), (b), and (c) NH —CH₃ —H —Cl E507(a), (b), and (c) NH —CH₃ —H—Br E508(a), (b), and (c) NH —CH₃ —H —F E509(a), (b), and (c) NH —CH₃ —H—CH₃ E510(a), (b), and (c) NH —CH₃ —H —CF₃ E511(a), (b), and (c) NH —CH₃—H —OCH₃ E512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ E513(a), (b), and (c)NH —CH₃ —H —OCF₃ E514(a), (b), and (c) NH —CH₃ —H -tert-butyl E515(a),(b), and (c) NH —CH₃ —H -iso-propyl E516(a), (b), and (c) NH —CF₃ —Cl —HE517(a), (b), and (c) NH —CF₃ —Br —H E518(a), (b), and (c) NH —CF₃ —F —HE519(a), (b), and (c) NH —CF₃ —CH₃ —H E520(a), (b), and (c) NH —CF₃ —CF₃—H E521(a), (b), and (c) NH —CF₃ —OCH₃ —H E522(a), (b), and (c) NH —CF₃—OCH₂CH₃ —H E523(a), (b), and (c) NH —CF₃ —OCF₃ —H E524(a), (b), and (c)NH —CF₃ -tert-butyl —H E525(a), (b), and (c) NH —CF₃ -iso-propyl —HE526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ E527(a), (b), and (c) NH —CF₃ —H—H E528(a), (b), and (c) NH —CF₃ —H —Cl E529(a), (b), and (c) NH —CF₃ —H—Br E530(a), (b), and (c) NH —CF₃ —H —F E531(a), (b), and (c) NH —CF₃ —H—CH₃ E532(a), (b), and (c) NH —CF₃ —H —CF₃ E533(a), (b), and (c) NH —CF₃—H —OCH₃ E534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ E535(a), (b), and (c)NH —CF₃ —H —OCF₃ E536(a), (b), and (c) NH —CF₃ —H -tert-butyl E537(a),(b), and (c) NH —CF₃ —H -iso-propyl E538(a), (b), and (c) NH —CHF₂ —Cl—H E539(a), (b), and (c) NH —CHF₂ —Br —H E540(a), (b), and (c) NH —CHF₂—F —H E541(a), (b), and (c) NH —CHF₂ —CH₃ —H E542(a), (b), and (c) NH—CHF₂ —CF₃ —H E543(a), (b), and (c) NH —CHF₂ —OCH₃ —H E544(a), (b), and(c) NH —CHF₂ —OCH₂CH₃ —H E545(a), (b), and (c) NH —CHF₂ —OCF₃ —HE546(a), (b), and (c) NH —CHF₂ -tert-butyl —H E547(a), (b), and (c) NH—CHF₂ -iso-propyl —H E548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ E549(a),(b), and (c) NH —CHF₂ —H —H E550(a), (b), and (c) NH —CHF₂ —H —ClE551(a), (b), and (c) NH —CHF₂ —H —Br E552(a), (b), and (c) NH —CHF₂ —H—F E553(a), (b), and (c) NH —CHF₂ —H —CH₃ E554(a), (b), and (c) NH —CHF₂—H —CF₃ E555(a), (b), and (c) NH —CHF₂ —H —OCH₃ E556(a), (b), and (c) NH—CHF₂ —H —OCH₂CH₃ E557(a), (b), and (c) NH —CHF₂ —H —OCF₃ E558(a), (b),and (c) NH —CHF₂ —H -tert-butyl E559(a), (b), and (c) NH —CHF₂ —H-iso-propyl E560(a), (b), and (c) NH —OH —Cl —H E561(a), (b), and (c) NH—OH —Br —H E562(a), (b), and (c) NH —OH —F —H E563(a), (b), and (c) NH—OH —CH₃ —H E564(a), (b), and (c) NH —OH —CF₃ —H E565(a), (b), and (c)NH —OH —OCH₃ —H E566(a), (b), and (c) NH —OH —OCH₂CH₃ —H E567(a), (b),and (c) NH —OH —OCF₃ —H E568(a), (b), and (c) NH —OH -tert-butyl —HE569(a), (b), and (c) NH —OH -iso-propyl —H E570(a), (b), and (c) NH —OH—CH₃ —CH₃ E571(a), (b), and (c) NH —OH —H —H E572(a), (b), and (c) NH—OH —H —Cl E573(a), (b), and (c) NH —OH —H —Br E574(a), (b), and (c) NH—OH —H —F E575(a), (b), and (c) NH —OH —H —CH₃ E576(a), (b), and (c) NH—OH —H —CF₃ E577(a), (b), and (c) NH —OH —H —OCH₃ E578(a), (b), and (c)NH —OH —H —OCH₂CH₃ E579(a), (b), and (c) NH —OH —H —OCF₃ E580(a), (b),and (c) NH —OH —H -tert-butyl E581(a), (b), and (c) NH —OH —H-iso-propyl E582(a), (b), and (c) NH —NO₂ —Cl —H E583(a), (b), and (c)NH —NO₂ —Br —H E584(a), (b), and (c) NH —NO₂ —F —H E585(a), (b), and (c)NH —NO₂ —CH₃ —H E586(a), (b), and (c) NH —NO₂ —CF₃ —H E587(a), (b), and(c) NH —NO₂ —OCH₃ —H E588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H E589(a),(b), and (c) NH —NO₂ —OCF₃ —H E590(a), (b), and (c) NH —NO₂ -tert-butyl—H E591(a), (b), and (c) NH —NO₂ -iso-propyl —H E592(a), (b), and (c) NH—NO₂ —CH₃ —CH₃ E593(a), (b), and (c) NH —NO₂ —H —H E594(a), (b), and (c)NH —NO₂ —H —Cl E595(a), (b), and (c) NH —NO₂ —H —Br E596(a), (b), and(c) NH —NO₂ —H —F E597(a), (b), and (c) NH —NO₂ —H —CH₃ E598(a), (b),and (c) NH —NO₂ —H —CF₃ E599(a), (b), and (c) NH —NO₂ —H —OCH₃ E600(a),(b), and (c) NH —NO₂ —H —OCH₂CH₃ E601(a), (b), and (c) NH —NO₂ —H —OCF₃E602(a), (b), and (c) NH —NO₂ —H -tert-butyl E603(a), (b), and (c) NH—NO₂ —H -iso-propyl E604(a), (b), and (c) NH —CN —Br —H E605(a), (b),and (c) NH —CN —Cl —H E606(a), (b), and (c) NH —CN —F —H E607(a), (b),and (c) NH —CN —CH₃ —H E608(a), (b), and (c) NH —CN —CF₃ —H E609(a),(b), and (c) NH —CN —OCH₃ —H E610(a), (b), and (c) NH —CN —OCH₂CH₃ —HE611(a), (b), and (c) NH —CN —OCF₃ —H E612(a), (b), and (c) NH —CN-tert-butyl —H E613(a), (b), and (c) NH —CN -iso-propyl —H E614(a), (b),and (c) NH —CN —CH₃ —CH₃ E615(a), (b), and (c) NH —CN —H —H E616(a),(b), and (c) NH —CN —H —Cl E617(a), (b), and (c) NH —CN —H —Br E618(a),(b), and (c) NH —CN —H —F E619(a), (b), and (c) NH —CN —H —CH₃ E620(a),(b), and (c) NH —CN —H —CF₃ E621(a), (b), and (c) NH —CN —H —OCH₃E622(a), (b), and (c) NH —CN —H —OCH₂CH₃ E623(a), (b), and (c) NH —CN —H—OCF₃ E624(a), (b), and (c) NH —CN —H -tert-butyl E625(a), (b), and (c)NH —CN —H -iso-propyl E626(a), (b), and (c) NH —Br —Br —H E627(a), (b),and (c) NH —Br —Cl —H E628(a), (b), and (c) NH —Br —F —H E629(a), (b),and (c) NH —Br —CH₃ —H E630(a), (b), and (c) NH —Br —CF₃ —H E631(a),(b), and (c) NH —Br —OCH₃ —H E632(a), (b), and (c) NH —Br —OCH₂CH₃ —HE633(a), (b), and (c) NH —Br —OCF₃ —H E634(a), (b), and (c) NH —Br-tert-butyl —H E635(a), (b), and (c) NH —Br -iso-propyl —H E636(a), (b),and (c) NH —Br —CH₃ —CH₃ E637(a), (b), and (c) NH —Br —H —H E638(a),(b), and (c) NH —Br —H —Cl E639(a), (b), and (c) NH —Br —H —Br E640(a),(b), and (c) NH —Br —H —F E641(a), (b), and (c) NH —Br —H —CH₃ E642(a),(b), and (c) NH —Br —H —CF₃ E643(a), (b), and (c) NH —Br —H —OCH₃E644(a), (b), and (c) NH —Br —H —OCH₂CH₃ E645(a), (b), and (c) NH —Br —H—OCF₃ E646(a), (b), and (c) NH —Br —H -tert-butyl E647(a), (b), and (c)NH —Br —H -iso-propyl E648(a), (b), and (c) NH —I —Cl —H E649(a), (b),and (c) NH —I —Br —H E650(a), (b), and (c) NH —I —F —H E651(a), (b), and(c) NH —I —CH₃ —H E652(a), (b), and (c) NH —I —CF₃ —H E653(a), (b), and(c) NH —I —OCH₃ —H E654(a), (b), and (c) NH —I —OCH₂CH₃ —H E655(a), (b),and (c) NH —I —OCF₃ —H E656(a), (b), and (c) NH —I -tert-butyl —HE657(a), (b), and (c) NH —I -iso-propyl —H E658(a), (b), and (c) NH —I—CH₃ —CH₃ E659(a), (b), and (c) NH —I —H —H E660(a), (b), and (c) NH —I—H —Cl E661(a), (b), and (c) NH —I —H —Br E662(a), (b), and (c) NH —I —H—F E663(a), (b), and (c) NH —I —H —CH₃ E664(a), (b), and (c) NH —I —H—CF₃ E665(a), (b), and (c) NH —I —H —OCH₃ E666(a), (b), and (c) NH —I —H—OCH₂CH₃ E667(a), (b), and (c) NH —I —H —OCF₃ E668(a), (b), and (c) NH—I —H -tert-butyl E669(a), (b), and (c) NH —I —H -iso-propyl (a) meansthat R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is—H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 6 (If)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁(R₈)_(a) (R₈)_(b) F01(a), (b), and (c) S —H —Cl —H F02(a), (b), and (c)S —H —Br —H F03(a), (b), and (c) S —H —F —H F04(a), (b), and (c) S —H—CH₃ —H F05(a), (b), and (c) S —H —CF₃ —H F06(a), (b), and (c) S —H—OCH₃ —H F07(a), (b), and (c) S —H —OCH₂CH₃ —H F08(a), (b), and (c) S —H—OCF₃ —H F09(a), (b), and (c) S —H -tert-butyl —H F10(a), (b), and (c) S—H -iso-propyl —H F11(a), (b), and (c) S —H —CH₃ —CH₃ F12(a), (b), and(c) S —H —H —H F13(a), (b), and (c) S —H —H —Cl F14(a), (b), and (c) S—H —H —Br F15(a), (b), and (c) S —H —H —F F16(a), (b), and (c) S —H —H—CH₃ F17(a), (b), and (c) S —H —H —CF₃ F18(a), (b), and (c) S —H —H—OCH₃ F19(a), (b), and (c) S —H —H —OCH₂CH₃ F20(a), (b), and (c) S —H —H—OCF₃ F21(a), (b), and (c) S —H —H -tert-butyl F22(a), (b), and (c) S —H—H -iso-propyl F23(a), (b), and (c) S —Cl —Cl —H F24(a), (b), and (c) S—Cl —Br —H F25(a), (b), and (c) S —Cl —F —H F26(a), (b), and (c) S —Cl—CH₃ —H F27(a), (b), and (c) S —Cl —CF₃ —H F28(a), (b), and (c) S —Cl—OCH₃ —H F29(a), (b), and (c) S —Cl —OCH₂CH₃ —H F30(a), (b), and (c) S—Cl —OCF₃ —H F31(a), (b), and (c) S —Cl -tert-butyl —H F32(a), (b), and(c) S —Cl -iso-propyl —H F33(a), (b), and (c) S —Cl —CH₃ —CH₃ F34(a),(b), and (c) S —Cl —H —H F35(a), (b), and (c) S —Cl —H —Cl F36(a), (b),and (c) S —Cl —H —Br F37(a), (b), and (c) S —Cl —H —F F38(a), (b), and(c) S —Cl —H —CH₃ F39(a), (b), and (c) S —Cl —H —CF₃ F40(a), (b), and(c) S —Cl —H —OCH₃ F41(a), (b), and (c) S —Cl —H —OCH₂CH₃ F42(a), (b),and (c) S —Cl —H —OCF₃ F43(a), (b), and (c) S —Cl —H -tert-butyl F44(a),(b), and (c) S —Cl —H -iso-propyl F45(a), (b), and (c) S —Cl —H —OCF₃F46(a), (b), and (c) S —Cl —H -tert-butyl F47(a), (b), and (c) S —Cl —H-iso-propyl F48(a), (b), and (c) S —CH₃ —Cl —H F49(a), (b), and (c) S—CH₃ —Br —H F50(a), (b), and (c) S —CH₃ —F —H F51(a), (b), and (c) S—CH₃ —CH₃ —H F52(a), (b), and (c) S —CH₃ —CF₃ —H F53(a), (b), and (c) S—CH₃ —OCH₃ —H F54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H F55(a), (b), and(c) S —CH₃ —OCF₃ —H F56(a), (b), and (c) S —CH₃ -tert-butyl —H F57(a),(b), and (c) S —CH₃ -iso-propyl —H F58(a), (b), and (c) S —CH₃ —CH₃ —CH₃F59(a), (b), and (c) S —CH₃ —H —H F60(a), (b), and (c) S —CH₃ —H —ClF61(a), (b), and (c) S —CH₃ —H —Br F62(a), (b), and (c) S —CH₃ —H —FF63(a), (b), and (c) S —CH₃ —H —CH₃ F64(a), (b), and (c) S —CH₃ —H —CF₃F65(a), (b), and (c) S —CH₃ —H —OCH₃ F66(a), (b), and (c) S —CH₃ —H—OCH₂CH₃ F67(a), (b), and (c) S —CH₃ —H —OCF₃ F68(a), (b), and (c) S—CH₃ —H -tert-butyl F69(a), (b), and (c) S —CH₃ —H -iso-propyl F70(a),(b), and (c) S —CF₃ —Cl —H F71(a), (b), and (c) S —CF₃ —Br —H F72(a),(b), and (c) S —CF₃ —F —H F73(a), (b), and (c) S —CF₃ —CH₃ —H F74(a),(b), and (c) S —CF₃ —CF₃ —H F75(a), (b), and (c) S —CF₃ —OCH₃ —H F76(a),(b), and (c) S —CF₃ —OCH₂CH₃ —H F77(a), (b), and (c) S —CF₃ —OCF₃ —HF78(a), (b), and (c) S —CF₃ -tert-butyl —H F79(a), (b), and (c) S —CF₃-iso-propyl —H F80(a), (b), and (c) S —CF₃ —CH₃ —CH₃ F81(a), (b), and(c) S —CF₃ —H —H F82(a), (b), and (c) S —CF₃ —H —Cl F83(a), (b), and (c)S —CF₃ —H —Br F84(a), (b), and (c) S —CF₃ —H —F F85(a), (b), and (c) S—CF₃ —H —CH₃ F86(a), (b), and (c) S —CF₃ —H —CF₃ F87(a), (b), and (c) S—CF₃ —H —OCH₃ F88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ F89(a), (b), and(c) S —CF₃ —H —OCF₃ F90(a), (b), and (c) S —CF₃ —H -tert-butyl F91(a),(b), and (c) S —CF₃ —H -iso-propyl F92(a), (b), and (c) S —CHF₂ —Cl —HF93(a), (b), and (c) S —CHF₂ —Br —H F94(a), (b), and (c) S —CHF₂ —F —HF95(a), (b), and (c) S —CHF₂ —CH₃ —H F96(a), (b), and (c) S —CHF₂ —CF₃—H F97(a), (b), and (c) S —CHF₂ —OCH₃ —H F98(a), (b), and (c) S —CHF₂—OCH₂CH₃ —H F99(a), (b), and (c) S —CHF₂ —OCF₃ —H F100(a), (b), and (c)S —CHF₂ -tert-butyl —H F101(a), (b), and (c) S —CHF₂ -iso-propyl —HF102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ F103(a), (b), and (c) S —CHF₂ —H—H F104(a), (b), and (c) S —CHF₂ —H —Cl F105(a), (b), and (c) S —CHF₂ —H—Br F106(a), (b), and (c) S —CHF₂ —H —F F107(a), (b), and (c) S —CHF₂ —H—CH₃ F108(a), (b), and (c) S —CHF₂ —H —CF₃ F109(a), (b), and (c) S —CHF₂—H —OCH₃ F110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ F111(a), (b), and (c)S —CHF₂ —H —OCF₃ F112(a), (b), and (c) S —CHF₂ —H -tert-butyl F113(a),(b), and (c) S —CHF₂ —H -iso-propyl F114(a), (b), and (c) S —OH —Cl —HF115(a), (b), and (c) S —OH —Br —H F116(a), (b), and (c) S —OH —F —HF117(a), (b), and (c) S —OH —CH₃ —H F118(a), (b), and (c) S —OH —CF₃ —HF119(a), (b), and (c) S —OH —OCH₃ —H F120(a), (b), and (c) S —OH—OCH₂CH₃ —H F121(a), (b), and (c) S —OH —OCF₃ —H F122(a), (b), and (c) S—OH -tert-butyl —H F123(a), (b), and (c) S —OH -iso-propyl —H F124(a),(b), and (c) S —OH —CH₃ —CH₃ F125(a), (b), and (c) S —OH —H —H F126(a),(b), and (c) S —OH —H —Cl F127(a), (b), and (c) S —OH —H —Br F128(a),(b), and (c) S —OH —H —F F129(a), (b), and (c) S —OH —H —CH₃ F130(a),(b), and (c) S —OH —H —CF₃ F131(a), (b), and (c) S —OH —H —OCH₃ F132(a),(b), and (c) S —OH —H —OCH₂CH₃ F133(a), (b), and (c) S —OH —H —OCF₃F134(a), (b), and (c) S —OH —H -tert-butyl F135(a), (b), and (c) S —OH—H -iso-propyl F136(a), (b), and (c) S —NO₂ —Cl —H F137(a), (b), and (c)S —NO₂ —Br —H F138(a), (b), and (c) S —NO₂ —F —H F139(a), (b), and (c) S—NO₂ —CH₃ —H F140(a), (b), and (c) S —NO₂ —CF₃ —H F141(a), (b), and (c)S —NO₂ —OCH₃ —H F142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H F143(a), (b),and (c) S —NO₂ —OCF₃ —H F144(a), (b), and (c) S —NO₂ -tert-butyl —HF145(a), (b), and (c) S —NO₂ -iso-propyl —H F146(a), (b), and (c) S —NO₂—CH₃ —CH₃ F147(a), (b), and (c) S —NO₂ —H —H F148(a), (b), and (c) S—NO₂ —H —Cl F149(a), (b), and (c) S —NO₂ —H —Br F150(a), (b), and (c) S—NO₂ —H —F F151(a), (b), and (c) S —NO₂ —H —CH₃ F152(a), (b), and (c) S—NO₂ —H —CF₃ F153(a), (b), and (c) S —NO₂ —H —OCH₃ F154(a), (b), and (c)S —NO₂ —H —OCH₂CH₃ F155(a), (b), and (c) S —NO₂ —H —OCF₃ F156(a), (b),and (c) S —NO₂ —H -tert-butyl F157(a), (b), and (c) S —NO₂ —H-iso-propyl F158(a), (b), and (c) S —CN —Br —H F159(a), (b), and (c) S—CN —Cl —H F160(a), (b), and (c) S —CN —F —H F161(a), (b), and (c) S —CN—CH₃ —H F162(a), (b), and (c) S —CN —CF₃ —H F163(a), (b), and (c) S —CN—OCH₃ —H F164(a), (b), and (c) S —CN —OCH₂CH₃ —H F165(a), (b), and (c) S—CN —OCF₃ —H F166(a), (b), and (c) S —CN -tert-butyl —H F167(a), (b),and (c) S —CN -iso-propyl —H F168(a), (b), and (c) S —CN —CH₃ —CH₃F169(a), (b), and (c) S —CN —H —H F170(a), (b), and (c) S —CN —H —ClF171(a), (b), and (c) S —CN —H —Br F172(a), (b), and (c) S —CN —H —FF173(a), (b), and (c) S —CN —H —CH₃ F174(a), (b), and (c) S —CN —H —CF₃F175(a), (b), and (c) S —CN —H —OCH₃ F176(a), (b), and (c) S —CN —H—OCH₂CH₃ F177(a), (b), and (c) S —CN —H —OCF₃ F178(a), (b), and (c) S—CN —H -tert-butyl F179(a), (b), and (c) S —CN —H -iso-propyl F180(a),(b), and (c) S —Br —Br —H F181(a), (b), and (c) S —Br —Cl —H F182(a),(b), and (c) S —Br —F —H F183(a), (b), and (c) S —Br —CH₃ —H F184(a),(b), and (c) S —Br —CF₃ —H F185(a), (b), and (c) S —Br —OCH₃ —H F186(a),(b), and (c) S —Br —OCH₂CH₃ —H F187(a), (b), and (c) S —Br —OCF₃ —HF188(a), (b), and (c) S —Br -tert-butyl —H F189(a), (b), and (c) S —Br-iso-propyl —H F190(a), (b), and (c) S —Br —CH₃ —CH₃ F191(a), (b), and(c) S —Br —H —H F192(a), (b), and (c) S —Br —H —Cl F193(a), (b), and (c)S —Br —H —Br F194(a), (b), and (c) S —Br —H —F F195(a), (b), and (c) S—Br —H —CH₃ F196(a), (b), and (c) S —Br —H —CF₃ F197(a), (b), and (c) S—Br —H —OCH₃ F198(a), (b), and (c) S —Br —H —OCH₂CH₃ F199(a), (b), and(c) S —Br —H —OCF₃ F200(a), (b), and (c) S —Br —H -tert-butyl F201(a),(b), and (c) S —Br —H -iso-propyl F202(a), (b), and (c) S —I —Cl —HF203(a), (b), and (c) S —I —Br —H F204(a), (b), and (c) S —I —F —HF205(a), (b), and (c) S —I —CH₃ —H F206(a), (b), and (c) S —I —CF₃ —HF207(a), (b), and (c) S —I —OCH₃ —H F208(a), (b), and (c) S —I —OCH₂CH₃—H F209(a), (b), and (c) S —I —OCF₃ —H F210(a), (b), and (c) S —I-tert-butyl —H F211(a), (b), and (c) S —I -iso-propyl —H F212(a), (b),and (c) S —I —CH₃ —CH₃ F213(a), (b), and (c) S —I —H —H F214(a), (b),and (c) S —I —H —Cl F215(a), (b), and (c) S —I —H —Br F216(a), (b), and(c) S —I —H —F F217(a), (b), and (c) S —I —H —CH₃ F218(a), (b), and (c)S —I —H —CF₃ F219(a), (b), and (c) S —I —H —OCH₃ F220(a), (b), and (c) S—I —H —OCH₂CH₃ F221(a), (b), and (c) S —I —H —OCF₃ F222(a), (b), and (c)S —I —H -tert-butyl F223(a), (b), and (c) S —I —H -iso-propyl F224(a),(b), and (c) O —H —Cl —H F225(a), (b), and (c) O —H —Br —H F226(a), (b),and (c) O —H —F —H F227(a), (b), and (c) O —H —CH₃ —H F228(a), (b), and(c) O —H —CF₃ —H F229(a), (b), and (c) O —H —OCH₃ —H F230(a), (b), and(c) O —H —OCH₂CH₃ —H F231(a), (b), and (c) O —H —OCF₃ —H F232(a), (b),and (c) O —H -tert-butyl —H F233(a), (b), and (c) O —H -iso-propyl —HF234(a), (b), and (c) O —H —CH₃ —CH₃ F235(a), (b), and (c) O —H —H —HF236(a), (b), and (c) O —H —H —Cl F237(a), (b), and (c) O —H —H —BrF238(a), (b), and (c) O —H —H —F F239(a), (b), and (c) O —H —H —CH₃F240(a), (b), and (c) O —H —H —CF₃ F241(a), (b), and (c) O —H —H —OCH₃F242(a), (b), and (c) O —H —H —OCH₂CH₃ F243(a), (b), and (c) O —H —H—OCF₃ F244(a), (b), and (c) O —H —H -tert-butyl F245(a), (b), and (c) O—H —H -iso-propyl F246(a), (b), and (c) O —Cl —Cl —H F247(a), (b), and(c) O —Cl —Br —H F248(a), (b), and (c) O —Cl —F —H F249(a), (b), and (c)O —Cl —CH₃ —H F250(a), (b), and (c) O —Cl —CF₃ —H F251(a), (b), and (c)O —Cl —OCH₃ —H F252(a), (b), and (c) O —Cl —OCH₂CH₃ —H F253(a), (b), and(c) O —Cl —OCF₃ —H F254(a), (b), and (c) O —Cl -tert-butyl —H F255(a),(b), and (c) O —Cl -iso-propyl —H F256(a), (b), and (c) O —Cl —CH₃ —CH₃F257(a), (b), and (c) O —Cl —H —H F258(a), (b), and (c) O —Cl —H —CH₃F259(a), (b), and (c) O —Cl —H —Cl F260(a), (b), and (c) O —Cl —H —BrF261(a), (b), and (c) O —Cl —H —F F262(a), (b), and (c) O —Cl —H —CF₃F263(a), (b), and (c) O —Cl —H —OCH₃ F264(a), (b), and (c) O —Cl —H—OCH₂CH₃ F265(a), (b), and (c) O —Cl —H —OCF₃ F266(a), (b), and (c) O—Cl —H -tert-butyl F267(a), (b), and (c) O —Cl —H -iso-propyl F268(a),(b), and (c) O —Cl —H —OCF₃ F269(a), (b), and (c) O —Cl —H -tert-butylF270(a), (b), and (c) O —Cl —H -iso-propyl F271(a), (b), and (c) O —CH₃—Cl —H F272(a), (b), and (c) O —CH₃ —Br —H F273(a), (b), and (c) O —CH₃—F —H F274(a), (b), and (c) O —CH₃ —CH₃ —H F275(a), (b), and (c) O —CH₃—CF₃ —H F276(a), (b), and (c) O —CH₃ —OCH₃ —H F277(a), (b), and (c) O—CH₃ —OCH₂CH₃ —H F278(a), (b), and (c) O —CH₃ —OCF₃ —H F279(a), (b), and(c) O —CH₃ -tert-butyl —H F280(a), (b), and (c) O —CH₃ -iso-propyl —HF281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ F282(a), (b), and (c) O —CH₃ —H—H F283(a), (b), and (c) O —CH₃ —H —Cl F284(a), (b), and (c) O —CH₃ —H—Br F285(a), (b), and (c) O —CH₃ —H —F F286(a), (b), and (c) O —CH₃ —H—CH₃ F287(a), (b), and (c) O —CH₃ —H —CF₃ F288(a), (b), and (c) O —CH₃—H —OCH₃ F289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ F290(a), (b), and (c)O —CH₃ —H —OCF₃ F291(a), (b), and (c) O —CH₃ —H -tert-butyl F292(a),(b), and (c) O —CH₃ —H -iso-propyl F293(a), (b), and (c) O —CF₃ —Cl —HF294(a), (b), and (c) O —CF₃ —Br —H F295(a), (b), and (c) O —CF₃ —F —HF296(a), (b), and (c) O —CF₃ —CH₃ —H F297(a), (b), and (c) O —CF₃ —CF₃—H F298(a), (b), and (c) O —CF₃ —OCH₃ —H F299(a), (b), and (c) O —CF₃—OCH₂CH₃ —H F300(a), (b), and (c) O —CF₃ —OCF₃ —H F301(a), (b), and (c)O —CF₃ -tert-butyl —H F302(a), (b), and (c) O —CF₃ -iso-propyl —HF303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ F304(a), (b), and (c) O —CF₃ —H—H F305(a), (b), and (c) O —CF₃ —H —Cl F306(a), (b), and (c) O —CF₃ —H—Br F307(a), (b), and (c) O —CF₃ —H —F F308(a), (b), and (c) O —CF₃ —H—CH₃ F309(a), (b), and (c) O —CF₃ —H —CF₃ F310(a), (b), and (c) O —CF₃—H —OCH₃ F311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ F312(a), (b), and (c)O —CF₃ —H —OCF₃ F313(a), (b), and (c) O —CF₃ —H -tert-butyl F314(a),(b), and (c) O —CF₃ —H -iso-propyl F315(a), (b), and (c) O —CHF₂ —Cl —HF316(a), (b), and (c) O —CHF₂ —Br —H F317(a), (b), and (c) O —CHF₂ —F —HF318(a), (b), and (c) O —CHF₂ —CH₃ —H F319(a), (b), and (c) O —CHF₂ —CF₃—H F320(a), (b), and (c) O —CHF₂ —OCH₃ —H F321(a), (b), and (c) O —CHF₂—OCH₂CH₃ —H F322(a), (b), and (c) O —CHF₂ —OCF₃ —H F323(a), (b), and (c)O —CHF₂ -tert-butyl —H F324(a), (b), and (c) O —CHF₂ -iso-propyl —HF325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ F326(a), (b), and (c) O —CHF₂ —H—H F327(a), (b), and (c) O —CHF₂ —H —Cl F328(a), (b), and (c) O —CHF₂ —H—Br F329(a), (b), and (c) O —CHF₂ —H —F F330(a), (b), and (c) O —CHF₂ —H—CH₃ F331(a), (b), and (c) O —CHF₂ —H —CF₃ F332(a), (b), and (c) O —CHF₂—H —OCH₃ F333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ F334(a), (b), and (c)O —CHF₂ —H —OCF₃ F335(a), (b), and (c) O —CHF₂ —H -tert-butyl F336(a),(b), and (c) O —CHF₂ —H -iso-propyl F337(a), (b), and (c) O —OH —Cl —HF338(a), (b), and (c) O —OH —Br —H F339(a), (b), and (c) O —OH —F —HF340(a), (b), and (c) O —OH —CH₃ —H F341(a), (b), and (c) O —OH —CF₃ —HF342(a), (b), and (c) O —OH —OCH₃ —H F343(a), (b), and (c) O —OH—OCH₂CH₃ —H F344(a), (b), and (c) O —OH —OCF₃ —H F345(a), (b), and (c) O—OH -tert-butyl —H F346(a), (b), and (c) O —OH -iso-propyl —H F347(a),(b), and (c) O —OH —CH₃ —CH₃ F348(a), (b), and (c) O —OH —H —H F349(a),(b), and (c) O —OH —H —Cl F350(a), (b), and (c) O —OH —H —Br F351(a),(b), and (c) O —OH —H —F F352(a), (b), and (c) O —OH —H —CH₃ F353(a),(b), and (c) O —OH —H —CF₃ F354(a), (b), and (c) O —OH —H —OCH₃ F355(a),(b), and (c) O —OH —H —OCH₂CH₃ F356(a), (b), and (c) O —OH —H —OCF₃F357(a), (b), and (c) O —OH —H -tert-butyl F358(a), (b), and (c) O —OH—H -iso-propyl F359(a), (b), and (c) O —NO₂ —Cl —H F360(a), (b), and (c)O —NO₂ —Br —H F361(a), (b), and (c) O —NO₂ —F —H F362(a), (b), and (c) O—NO₂ —CH₃ —H F363(a), (b), and (c) O —NO₂ —CF₃ —H F364(a), (b), and (c)O —NO₂ —OCH₃ —H F365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H F366(a), (b),and (c) O —NO₂ —OCF₃ —H F367(a), (b), and (c) O —NO₂ -tert-butyl —HF368(a), (b), and (c) O —NO₂ -iso-propyl —H F369(a), (b), and (c) O —NO₂—CH₃ —CH₃ F370(a), (b), and (c) O —NO₂ —H —H F371(a), (b), and (c) O—NO₂ —H —Cl F372(a), (b), and (c) O —NO₂ —H —Br F373(a), (b), and (c) O—NO₂ —H —F F374(a), (b), and (c) O —NO₂ —H —CH₃ F375(a), (b), and (c) O—NO₂ —H —CF₃ F376(a), (b), and (c) O —NO₂ —H —OCH₃ F377(a), (b), and (c)O —NO₂ —H —OCH₂CH₃ F378(a), (b), and (c) O —NO₂ —H —OCF₃ F379(a), (b),and (c) O —NO₂ —H -tert-butyl F380(a), (b), and (c) O —NO₂ —H-iso-propyl F381(a), (b), and (c) O —CN —Br —H F382(a), (b), and (c) O—CN —Cl —H F383(a), (b), and (c) O —CN —F —H F384(a), (b), and (c) O —CN—CH₃ —H F385(a), (b), and (c) O —CN —CF₃ —H F386(a), (b), and (c) O —CN—OCH₃ —H F387(a), (b), and (c) O —CN —OCH₂CH₃ —H F388(a), (b), and (c) O—CN —OCF₃ —H F389(a), (b), and (c) O —CN -tert-butyl —H F390(a), (b),and (c) O —CN -iso-propyl —H F391(a), (b), and (c) O —CN —CH₃ —CH₃F392(a), (b), and (c) O —CN —H —H F393(a), (b), and (c) O —CN —H —ClF394(a), (b), and (c) O —CN —H —Br F395(a), (b), and (c) O —CN —H —FF396(a), (b), and (c) O —CN —H —CH₃ F397(a), (b), and (c) O —CN —H —CF₃F398(a), (b), and (c) O —CN —H —OCH₃ F399(a), (b), and (c) O —CN —H—OCH₂CH₃ F400(a), (b), and (c) O —CN —H —OCF₃ F401(a), (b), and (c) O—CN —H -tert-butyl F402(a), (b), and (c) O —CN —H -iso-propyl F403(a),(b), and (c) O —Br —Br —H F404(a), (b), and (c) O —Br —Cl —H F405(a),(b), and (c) O —Br —F —H F406(a), (b), and (c) O —Br —CH₃ —H F407(a),(b), and (c) O —Br —CF₃ —H F408(a), (b), and (c) O —Br —OCH₃ —H F409(a),(b), and (c) O —Br —OCH₂CH₃ —H F410(a), (b), and (c) O —Br —OCF₃ —HF411(a), (b), and (c) O —Br -tert-butyl —H F412(a), (b), and (c) O —Br-iso-propyl —H F413(a), (b), and (c) O —Br —CH₃ —CH₃ F414(a), (b), and(c) O —Br —H —H F415(a), (b), and (c) O —Br —H —Cl F416(a), (b), and (c)O —Br —H —Br F417(a), (b), and (c) O —Br —H —F F418(a), (b), and (c) O—Br —H —CH₃ F419(a), (b), and (c) O —Br —H —CF₃ F420(a), (b), and (c) O—Br —H —OCH₃ F421(a), (b), and (c) O —Br —H —OCH₂CH₃ F422(a), (b), and(c) O —Br —H —OCF₃ F423(a), (b), and (c) O —Br —H -tert-butyl F424(a),(b), and (c) O —Br —H -iso-propyl F425(a), (b), and (c) O —I —Br —HF426(a), (b), and (c) O —I —Cl —H F427(a), (b), and (c) O —I —F —HF428(a), (b), and (c) O —I —CH₃ —H F429(a), (b), and (c) O —I —CF₃ —HF430(a), (b), and (c) O —I —OCH₃ —H F431(a), (b), and (c) O —I —OCH₂CH₃—H F432(a), (b), and (c) O —I —OCF₃ —H F433(a), (b), and (c) O —I-tert-butyl —H F434(a), (b), and (c) O —I -iso-propyl —H F435(a), (b),and (c) O —I —CH₃ —CH₃ F436(a), (b), and (c) O —I —H —H F437(a), (b),and (c) O —I —H —Cl F438(a), (b), and (c) O —I —H —Br F439(a), (b), and(c) O —I —H —F F440(a), (b), and (c) O —I —H —CH₃ F441(a), (b), and (c)O —I —H —CF₃ F442(a), (b), and (c) O —I —H —OCH₃ F443(a), (b), and (c) O—I —H —OCH₂CH₃ F444(a), (b), and (c) O —I —H —OCF₃ F445(a), (b), and (c)O —I —H -tert-butyl F446(a), (b), and (c) O —I —H -iso-propyl F447(a),(b), and (c) NH —H —Cl —H F448(a), (b), and (c) NH —H —Br —H F449(a),(b), and (c) NH —H —F —H F450(a), (b), and (c) NH —H —CH₃ —H F451(a),(b), and (c) NH —H —CF₃ —H F452(a), (b), and (c) NH —H —OCH₃ —H F453(a),(b), and (c) NH —H —OCH₂CH₃ —H F454(a), (b), and (c) NH —H —OCF₃ —HF455(a), (b), and (c) NH —H -tert-butyl —H F456(a), (b), and (c) NH —H-iso-propyl —H F457(a), (b), and (c) NH —H —CH₃ —CH₃ F458(a), (b), and(c) NH —H —H —H F459(a), (b), and (c) NH —H —H —Cl F460(a), (b), and (c)NH —H —H —Br F461(a), (b), and (c) NH —H —H —F F462(a), (b), and (c) NH—H —H —CH₃ F463(a), (b), and (c) NH —H —H —CF₃ F464(a), (b), and (c) NH—H —H —OCH₃ F465(a), (b), and (c) NH —H —H —OCH₂CH₃ F466(a), (b), and(c) NH —H —H —OCF₃ F467(a), (b), and (c) NH —H —H -tert-butyl F468(a),(b), and (c) NH —H —H -iso-propyl F469(a), (b), and (c) NH —Cl —Cl —HF470(a), (b), and (c) NH —Cl —Br —H F471(a), (b), and (c) NH —Cl —F —HF472(a), (b), and (c) NH —Cl —CH₃ —H F473(a), (b), and (c) NH —Cl —CF₃—H F474(a), (b), and (c) NH —Cl —OCH₃ —H F475(a), (b), and (c) NH —Cl—OCH₂CH₃ —H F476(a), (b), and (c) NH —Cl —OCF₃ —H F477(a), (b), and (c)NH —Cl -tert-butyl —H F478(a), (b), and (c) NH —Cl -iso-propyl —HF479(a), (b), and (c) NH —Cl —CH₃ —CH₃ F480(a), (b), and (c) NH —Cl —H—H F481(a), (b), and (c) NH —Cl —H —CH₃ F482(a), (b), and (c) NH —Cl —H—Cl F483(a), (b), and (c) NH —Cl —H —Br F484(a), (b), and (c) NH —Cl —H—F F485(a), (b), and (c) NH —Cl —H —CF₃ F486(a), (b), and (c) NH —Cl —H—OCH₃ F487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ F488(a), (b), and (c) NH—Cl —H —OCF₃ F489(a), (b), and (c) NH —Cl —H -tert-butyl F490(a), (b),and (c) NH —Cl —H -iso-propyl F491(a), (b), and (c) NH —Cl —H —OCF₃F492(a), (b), and (c) NH —Cl —H -tert-butyl F493(a), (b), and (c) NH —Cl—H -iso-propyl F494(a), (b), and (c) NH —CH₃ —Cl —H F495(a), (b), and(c) NH —CH₃ —Br —H F496(a), (b), and (c) NH —CH₃ —F —H F497(a), (b), and(c) NH —CH₃ —CH₃ —H F498(a), (b), and (c) NH —CH₃ —CF₃ —H F499(a), (b),and (c) NH —CH₃ —OCH₃ —H F500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —HF501(a), (b), and (c) NH —CH₃ —OCF₃ —H F502(a), (b), and (c) NH —CH₃-tert-butyl —H F503(a), (b), and (c) NH —CH₃ -iso-propyl —H F504(a),(b), and (c) NH —CH₃ —CH₃ —CH₃ F505(a), (b), and (c) NH —CH₃ —H —HF506(a), (b), and (c) NH —CH₃ —H —Cl F507(a), (b), and (c) NH —CH₃ —H—Br F508(a), (b), and (c) NH —CH₃ —H —F F509(a), (b), and (c) NH —CH₃ —H—CH₃ F510(a), (b), and (c) NH —CH₃ —H —CF₃ F511(a), (b), and (c) NH —CH₃—H —OCH₃ F512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ F513(a), (b), and (c)NH —CH₃ —H —OCF₃ F514(a), (b), and (c) NH —CH₃ —H -tert-butyl F515(a),(b), and (c) NH —CH₃ —H -iso-propyl F516(a), (b), and (c) NH —CF₃ —Cl —HF517(a), (b), and (c) NH —CF₃ —Br —H F518(a), (b), and (c) NH —CF₃ —F —HF519(a), (b), and (c) NH —CF₃ —CH₃ —H F520(a), (b), and (c) NH —CF₃ —CF₃—H F521(a), (b), and (c) NH —CF₃ —OCH₃ —H F522(a), (b), and (c) NH —CF₃—OCH₂CH₃ —H F523(a), (b), and (c) NH —CF₃ —OCF₃ —H F524(a), (b), and (c)NH —CF₃ -tert-butyl —H F525(a), (b), and (c) NH —CF₃ -iso-propyl —HF526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ F527(a), (b), and (c) NH —CF₃ —H—H F528(a), (b), and (c) NH —CF₃ —H —Cl F529(a), (b), and (c) NH —CF₃ —H—Br F530(a), (b), and (c) NH —CF₃ —H —F F531(a), (b), and (c) NH —CF₃ —H—CH₃ F532(a), (b), and (c) NH —CF₃ —H —CF₃ F533(a), (b), and (c) NH —CF₃—H —OCH₃ F534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ F535(a), (b), and (c)NH —CF₃ —H —OCF₃ F536(a), (b), and (c) NH —CF₃ —H -tert-butyl F537(a),(b), and (c) NH —CF₃ —H -iso-propyl F538(a), (b), and (c) NH —CHF₂ —Cl—H F539(a), (b), and (c) NH —CHF₂ —Br —H F540(a), (b), and (c) NH —CHF₂—F —H F541(a), (b), and (c) NH —CHF₂ —CH₃ —H F542(a), (b), and (c) NH—CHF₂ —CF₃ —H F543(a), (b), and (c) NH —CHF₂ —OCH₃ —H F544(a), (b), and(c) NH —CHF₂ —OCH₂CH₃ —H F545(a), (b), and (c) NH —CHF₂ —OCF₃ —HF546(a), (b), and (c) NH —CHF₂ -tert-butyl —H F547(a), (b), and (c) NH—CHF₂ -iso-propyl —H F548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ F549(a),(b), and (c) NH —CHF₂ —H —H F550(a), (b), and (c) NH —CHF₂ —H —ClF551(a), (b), and (c) NH —CHF₂ —H —Br F552(a), (b), and (c) NH —CHF₂ —H—F F553(a), (b), and (c) NH —CHF₂ —H —CH₃ F554(a), (b), and (c) NH —CHF₂—H —CF₃ F555(a), (b), and (c) NH —CHF₂ —H —OCH₃ F556(a), (b), and (c) NH—CHF₂ —H —OCH₂CH₃ F557(a), (b), and (c) NH —CHF₂ —H —OCF₃ F558(a), (b),and (c) NH —CHF₂ —H -tert-butyl F559(a), (b), and (c) NH —CHF₂ —H-iso-propyl F560(a), (b), and (c) NH —OH —Cl —H F561(a), (b), and (c) NH—OH —Br —H F562(a), (b), and (c) NH —OH —F —H F563(a), (b), and (c) NH—OH —CH₃ —H F564(a), (b), and (c) NH —OH —CF₃ —H F565(a), (b), and (c)NH —OH —OCH₃ —H F566(a), (b), and (c) NH —OH —OCH₂CH₃ —H F567(a), (b),and (c) NH —OH —OCF₃ —H F568(a), (b), and (c) NH —OH -tert-butyl —HF569(a), (b), and (c) NH —OH -iso-propyl —H F570(a), (b), and (c) NH —OH—CH₃ —CH₃ F571(a), (b), and (c) NH —OH —H —H F572(a), (b), and (c) NH—OH —H —Cl F573(a), (b), and (c) NH —OH —H —Br F574(a), (b), and (c) NH—OH —H —F F575(a), (b), and (c) NH —OH —H —CH₃ F576(a), (b), and (c) NH—OH —H —CF₃ F577(a), (b), and (c) NH —OH —H —OCH₃ F578(a), (b), and (c)NH —OH —H —OCH₂CH₃ F579(a), (b), and (c) NH —OH —H —OCF₃ F580(a), (b),and (c) NH —OH —H -tert-butyl F581(a), (b), and (c) NH —OH —H-iso-propyl F582(a), (b), and (c) NH —NO₂ —Cl —H F583(a), (b), and (c)NH —NO₂ —Br —H F584(a), (b), and (c) NH —NO₂ —F —H F585(a), (b), and (c)NH —NO₂ —CH₃ —H F586(a), (b), and (c) NH —NO₂ —CF₃ —H F587(a), (b), and(c) NH —NO₂ —OCH₃ —H F588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H F589(a),(b), and (c) NH —NO₂ —OCF₃ —H F590(a), (b), and (c) NH —NO₂ -tert-butyl—H F591(a), (b), and (c) NH —NO₂ -iso-propyl —H F592(a), (b), and (c) NH—NO₂ —CH₃ —CH₃ F593(a), (b), and (c) NH —NO₂ —H —H F594(a), (b), and (c)NH —NO₂ —H —Cl F595(a), (b), and (c) NH —NO₂ —H —Br F596(a), (b), and(c) NH —NO₂ —H —F F597(a), (b), and (c) NH —NO₂ —H —CH₃ F598(a), (b),and (c) NH —NO₂ —H —CF₃ F599(a), (b), and (c) NH —NO₂ —H —OCH₃ F600(a),(b), and (c) NH —NO₂ —H —OCH₂CH₃ F601(a), (b), and (c) NH —NO₂ —H —OCF₃F602(a), (b), and (c) NH —NO₂ —H -tert-butyl F603(a), (b), and (c) NH—NO₂ —H -iso-propyl F604(a), (b), and (c) NH —CN —Br —H F605(a), (b),and (c) NH —CN —Cl —H F606(a), (b), and (c) NH —CN —F —H F607(a), (b),and (c) NH —CN —CH₃ —H F608(a), (b), and (c) NH —CN —CF₃ —H F609(a),(b), and (c) NH —CN —OCH₃ —H F610(a), (b), and (c) NH —CN —OCH₂CH₃ —HF611(a), (b), and (c) NH —CN —OCF₃ —H F612(a), (b), and (c) NH —CN-tert-butyl —H F613(a), (b), and (c) NH —CN -iso-propyl —H F614(a), (b),and (c) NH —CN —CH₃ —CH₃ F615(a), (b), and (c) NH —CN —H —H F616(a),(b), and (c) NH —CN —H —Cl F617(a), (b), and (c) NH —CN —H —Br F618(a),(b), and (c) NH —CN —H —F F619(a), (b), and (c) NH —CN —H —CH₃ F620(a),(b), and (c) NH —CN —H —CF₃ F621(a), (b), and (c) NH —CN —H —OCH₃F622(a), (b), and (c) NH —CN —H —OCH₂CH₃ F623(a), (b), and (c) NH —CN —H—OCF₃ F624(a), (b), and (c) NH —CN —H -tert-butyl F625(a), (b), and (c)NH —CN —H -iso-propyl F626(a), (b), and (c) NH —Br —Br —H F627(a), (b),and (c) NH —Br —Cl —H F628(a), (b), and (c) NH —Br —F —H F629(a), (b),and (c) NH —Br —CH₃ —H F630(a), (b), and (c) NH —Br —CF₃ —H F631(a),(b), and (c) NH —Br —OCH₃ —H F632(a), (b), and (c) NH —Br —OCH₂CH₃ —HF633(a), (b), and (c) NH —Br —OCF₃ —H F634(a), (b), and (c) NH —Br-tert-butyl —H F635(a), (b), and (c) NH —Br -iso-propyl —H F636(a), (b),and (c) NH —Br —CH₃ —CH₃ F637(a), (b), and (c) NH —Br —H —H F638(a),(b), and (c) NH —Br —H —Cl F639(a), (b), and (c) NH —Br —H —Br F640(a),(b), and (c) NH —Br —H —F F641(a), (b), and (c) NH —Br —H —CH₃ F642(a),(b), and (c) NH —Br —H —CF₃ F643(a), (b), and (c) NH —Br —H —OCH₃F644(a), (b), and (c) NH —Br —H —OCH₂CH₃ F645(a), (b), and (c) NH —Br —H—OCF₃ F646(a), (b), and (c) NH —Br —H -tert-butyl F647(a), (b), and (c)NH —Br —H -iso-propyl F648(a), (b), and (c) NH —I —Cl —H F649(a), (b),and (c) NH —I —Br —H F650(a), (b), and (c) NH —I —F —H F651(a), (b), and(c) NH —I —CH₃ —H F652(a), (b), and (c) NH —I —CF₃ —H F653(a), (b), and(c) NH —I —OCH₃ —H F654(a), (b), and (c) NH —I —OCH₂CH₃ —H F655(a), (b),and (c) NH —I —OCF₃ —H F656(a), (b), and (c) NH —I -tert-butyl —HF657(a), (b), and (c) NH —I -iso-propyl —H F658(a), (b), and (c) NH —I—CH₃ —CH₃ F659(a), (b), and (c) NH —I —H —H F660(a), (b), and (c) NH —I—H —Cl F661(a), (b), and (c) NH —I —H —Br F662(a), (b), and (c) NH —I —H—F F663(a), (b), and (c) NH —I —H —CH₃ F664(a), (b), and (c) NH —I —H—CF₃ F665(a), (b), and (c) NH —I —H —OCH₃ F666(a), (b), and (c) NH —I —H—OCH₂CH₃ F667(a), (b), and (c) NH —I —H —OCF₃ F668(a), (b), and (c) NH—I —H -tert-butyl F669(a), (b), and (c) NH —I —H -iso-propyl (a) meansthat R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is—H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 7 (Ig)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁(R₈)_(a) (R₈)_(b) G01(a), (b), and (c) S —H —Cl —H G02(a), (b), and (c)S —H —Br —H G03(a), (b), and (c) S —H —F —H G04(a), (b), and (c) S —H—CH₃ —H G05(a), (b), and (c) S —H —CF₃ —H G06(a), (b), and (c) S —H—OCH₃ —H G07(a), (b), and (c) S —H —OCH₂CH₃ —H G08(a), (b), and (c) S —H—OCF₃ —H G09(a), (b), and (c) S —H -tert-butyl —H G10(a), (b), and (c) S—H -iso-propyl —H G11(a), (b), and (c) S —H —CH₃ —CH₃ G12(a), (b), and(c) S —H —H —H G13(a), (b), and (c) S —H —H —Cl G14(a), (b), and (c) S—H —H —Br G15(a), (b), and (c) S —H —H —F G16(a), (b), and (c) S —H —H—CH₃ G17(a), (b), and (c) S —H —H —CF₃ G18(a), (b), and (c) S —H —H—OCH₃ G19(a), (b), and (c) S —H —H —OCH₂CH₃ G20(a), (b), and (c) S —H —H—OCF₃ G21(a), (b), and (c) S —H —H -tert-butyl G22(a), (b), and (c) S —H—H -iso-propyl G23(a), (b), and (c) S —Cl —Cl —H G24(a), (b), and (c) S—Cl —Br —H G25(a), (b), and (c) S —Cl —F —H G26(a), (b), and (c) S —Cl—CH₃ —H G27(a), (b), and (c) S —Cl —CF₃ —H G28(a), (b), and (c) S —Cl—OCH₃ —H G29(a), (b), and (c) S —Cl —OCH₂CH₃ —H G30(a), (b), and (c) S—Cl —OCF₃ —H G31(a), (b), and (c) S —Cl -tert-butyl —H G32(a), (b), and(c) S —Cl -iso-propyl —H G33(a), (b), and (c) S —Cl —CH₃ —CH₃ G34(a),(b), and (c) S —Cl —H —H G35(a), (b), and (c) S —Cl —H —Cl G36(a), (b),and (c) S —Cl —H —Br G37(a), (b), and (c) S —Cl —H —F G38(a), (b), and(c) S —Cl —H —CH₃ G39(a), (b), and (c) S —Cl —H —CF₃ G40(a), (b), and(c) S —Cl —H —OCH₃ G41(a), (b), and (c) S —Cl —H —OCH₂CH₃ G42(a), (b),and (c) S —Cl —H —OCF₃ G43(a), (b), and (c) S —Cl —H -tert-butyl G44(a),(b), and (c) S —Cl —H -iso-propyl G45(a), (b), and (c) S —Cl —H —OCF₃G46(a), (b), and (c) S —Cl —H -tert-butyl G47(a), (b), and (c) S —Cl —H-iso-propyl G48(a), (b), and (c) S —CH₃ —Cl —H G49(a), (b), and (c) S—CH₃ —Br —H G50(a), (b), and (c) S —CH₃ —F —H G51(a), (b), and (c) S—CH₃ —CH₃ —H G52(a), (b), and (c) S —CH₃ —CF₃ —H G53(a), (b), and (c) S—CH₃ —OCH₃ —H G54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H G55(a), (b), and(c) S —CH₃ —OCF₃ —H G56(a), (b), and (c) S —CH₃ -tert-butyl —H G57(a),(b), and (c) S —CH₃ -iso-propyl —H G58(a), (b), and (c) S —CH₃ —CH₃ —CH₃G59(a), (b), and (c) S —CH₃ —H —H G60(a), (b), and (c) S —CH₃ —H —ClG61(a), (b), and (c) S —CH₃ —H —Br G62(a), (b), and (c) S —CH₃ —H —FG63(a), (b), and (c) S —CH₃ —H —CH₃ G64(a), (b), and (c) S —CH₃ —H —CF₃G65(a), (b), and (c) S —CH₃ —H —OCH₃ G66(a), (b), and (c) S —CH₃ —H—OCH₂CH₃ G67(a), (b), and (c) S —CH₃ —H —OCF₃ G68(a), (b), and (c) S—CH₃ —H -tert-butyl G69(a), (b), and (c) S —CH₃ —H -iso-propyl G70(a),(b), and (c) S —CF₃ —Cl —H G71(a), (b), and (c) S —CF₃ —Br —H G72(a),(b), and (c) S —CF₃ —F —H G73(a), (b), and (c) S —CF₃ —CH₃ —H G74(a),(b), and (c) S —CF₃ —CF₃ —H G75(a), (b), and (c) S —CF₃ —OCH₃ —H G76(a),(b), and (c) S —CF₃ —OCH₂CH₃ —H G77(a), (b), and (c) S —CF₃ —OCF₃ —HG78(a), (b), and (c) S —CF₃ -tert-butyl —H G79(a), (b), and (c) S —CF₃-iso-propyl —H G80(a), (b), and (c) S —CF₃ —CH₃ —CH₃ G81(a), (b), and(c) S —CF₃ —H —H G82(a), (b), and (c) S —CF₃ —H —Cl G83(a), (b), and (c)S —CF₃ —H —Br G84(a), (b), and (c) S —CF₃ —H —F G85(a), (b), and (c) S—CF₃ —H —CH₃ G86(a), (b), and (c) S —CF₃ —H —CF₃ G87(a), (b), and (c) S—CF₃ —H —OCH₃ G88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ G89(a), (b), and(c) S —CF₃ —H —OCF₃ G90(a), (b), and (c) S —CF₃ —H -tert-butyl G91(a),(b), and (c) S —CF₃ —H -iso-propyl G92(a), (b), and (c) S —CHF₂ —Cl —HG93(a), (b), and (c) S —CHF₂ —Br —H G94(a), (b), and (c) S —CHF₂ —F —HG95(a), (b), and (c) S —CHF₂ —CH₃ —H G96(a), (b), and (c) S —CHF₂ —CF₃—H G97(a), (b), and (c) S —CHF₂ —OCH₃ —H G98(a), (b), and (c) S —CHF₂—OCH₂CH₃ —H G99(a), (b), and (c) S —CHF₂ —OCF₃ —H G100(a), (b), and (c)S —CHF₂ -tert-butyl —H G101(a), (b), and (c) S —CHF₂ -iso-propyl —HG102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ G103(a), (b), and (c) S —CHF₂ —H—H G104(a), (b), and (c) S —CHF₂ —H —Cl G105(a), (b), and (c) S —CHF₂ —H—Br G106(a), (b), and (c) S —CHF₂ —H —F G107(a), (b), and (c) S —CHF₂ —H—CH₃ G108(a), (b), and (c) S —CHF₂ —H —CF₃ G109(a), (b), and (c) S —CHF₂—H —OCH₃ G110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ G111(a), (b), and (c)S —CHF₂ —H —OCF₃ G112(a), (b), and (c) S —CHF₂ —H -tert-butyl G113(a),(b), and (c) S —CHF₂ —H -iso-propyl G114(a), (b), and (c) S —OH —Cl —HG115(a), (b), and (c) S —OH —Br —H G116(a), (b), and (c) S —OH —F —HG117(a), (b), and (c) S —OH —CH₃ —H G118(a), (b), and (c) S —OH —CF₃ —HG119(a), (b), and (c) S —OH —OCH₃ —H G120(a), (b), and (c) S —OH—OCH₂CH₃ —H G121(a), (b), and (c) S —OH —OCF₃ —H G122(a), (b), and (c) S—OH -tert-butyl —H G123(a), (b), and (c) S —OH -iso-propyl —H G124(a),(b), and (c) S —OH —CH₃ —CH₃ G125(a), (b), and (c) S —OH —H —H G126(a),(b), and (c) S —OH —H —Cl G127(a), (b), and (c) S —OH —H —Br G128(a),(b), and (c) S —OH —H —F G129(a), (b), and (c) S —OH —H —CH₃ G130(a),(b), and (c) S —OH —H —CF₃ G131(a), (b), and (c) S —OH —H —OCH₃ G132(a),(b), and (c) S —OH —H —OCH₂CH₃ G133(a), (b), and (c) S —OH —H —OCF₃G134(a), (b), and (c) S —OH —H -tert-butyl G135(a), (b), and (c) S —OH—H -iso-propyl G136(a), (b), and (c) S —NO₂ —Cl —H G137(a), (b), and (c)S —NO₂ —Br —H G138(a), (b), and (c) S —NO₂ —F —H G139(a), (b), and (c) S—NO₂ —CH₃ —H G140(a), (b), and (c) S —NO₂ —CF₃ —H G141(a), (b), and (c)S —NO₂ —OCH₃ —H G142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H G143(a), (b),and (c) S —NO₂ —OCF₃ —H G144(a), (b), and (c) S —NO₂ -tert-butyl —HG145(a), (b), and (c) S —NO₂ -iso-propyl —H G146(a), (b), and (c) S —NO₂—CH₃ —CH₃ G147(a), (b), and (c) S —NO₂ —H —H G148(a), (b), and (c) S—NO₂ —H —Cl G149(a), (b), and (c) S —NO₂ —H —Br G150(a), (b), and (c) S—NO₂ —H —F G151(a), (b), and (c) S —NO₂ —H —CH₃ G152(a), (b), and (c) S—NO₂ —H —CF₃ G153(a), (b), and (c) S —NO₂ —H —OCH₃ G154(a), (b), and (c)S —NO₂ —H —OCH₂CH₃ G155(a), (b), and (c) S —NO₂ —H —OCF₃ G156(a), (b),and (c) S —NO₂ —H -tert-butyl G157(a), (b), and (c) S —NO₂ —H-iso-propyl G158(a), (b), and (c) S —CN —Br —H G159(a), (b), and (c) S—CN —Cl —H G160(a), (b), and (c) S —CN —F —H G161(a), (b), and (c) S —CN—CH₃ —H G162(a), (b), and (c) S —CN —CF₃ —H G163(a), (b), and (c) S —CN—OCH₃ —H G164(a), (b), and (c) S —CN —OCH₂CH₃ —H G165(a), (b), and (c) S—CN —OCF₃ —H G166(a), (b), and (c) S —CN -tert-butyl —H G167(a), (b),and (c) S —CN -iso-propyl —H G168(a), (b), and (c) S —CN —CH₃ —CH₃G169(a), (b), and (c) S —CN —H —H G170(a), (b), and (c) S —CN —H —ClG171(a), (b), and (c) S —CN —H —Br G172(a), (b), and (c) S —CN —H —FG173(a), (b), and (c) S —CN —H —CH₃ G174(a), (b), and (c) S —CN —H —CF₃G175(a), (b), and (c) S —CN —H —OCH₃ G176(a), (b), and (c) S —CN —H—OCH₂CH₃ G177(a), (b), and (c) S —CN —H —OCF₃ G178(a), (b), and (c) S—CN —H -tert-butyl G179(a), (b), and (c) S —CN —H -iso-propyl G180(a),(b), and (c) S —Br —Br —H G181(a), (b), and (c) S —Br —Cl —H G182(a),(b), and (c) S —Br —F —H G183(a), (b), and (c) S —Br —CH₃ —H G184(a),(b), and (c) S —Br —CF₃ —H G185(a), (b), and (c) S —Br —OCH₃ —H G186(a),(b), and (c) S —Br —OCH₂CH₃ —H G187(a), (b), and (c) S —Br —OCF₃ —HG188(a), (b), and (c) S —Br -tert-butyl —H G189(a), (b), and (c) S —Br-iso-propyl —H G190(a), (b), and (c) S —Br —CH₃ —CH₃ G191(a), (b), and(c) S —Br —H —H G192(a), (b), and (c) S —Br —H —Cl G193(a), (b), and (c)S —Br —H —Br G194(a), (b), and (c) S —Br —H —F G195(a), (b), and (c) S—Br —H —CH₃ G196(a), (b), and (c) S —Br —H —CF₃ G197(a), (b), and (c) S—Br —H —OCH₃ G198(a), (b), and (c) S —Br —H —OCH₂CH₃ G199(a), (b), and(c) S —Br —H —OCF₃ G200(a), (b), and (c) S —Br —H -tert-butyl G201(a),(b), and (c) S —Br —H -iso-propyl G202(a), (b), and (c) S —I —Cl —HG203(a), (b), and (c) S —I —Br —H G204(a), (b), and (c) S —I —F —HG205(a), (b), and (c) S —I —CH₃ —H G206(a), (b), and (c) S —I —CF₃ —HG207(a), (b), and (c) S —I —OCH₃ —H G208(a), (b), and (c) S —I —OCH₂CH₃—H G209(a), (b), and (c) S —I —OCF₃ —H G210(a), (b), and (c) S —I-tert-butyl —H G211(a), (b), and (c) S —I -iso-propyl —H G212(a), (b),and (c) S —I —CH₃ —CH₃ G213(a), (b), and (c) S —I —H —H G214(a), (b),and (c) S —I —H —Cl G215(a), (b), and (c) S —I —H —Br G216(a), (b), and(c) S —I —H —F G217(a), (b), and (c) S —I —H —CH₃ G218(a), (b), and (c)S —I —H —CF₃ G219(a), (b), and (c) S —I —H —OCH₃ G220(a), (b), and (c) S—I —H —OCH₂CH₃ G221(a), (b), and (c) S —I —H —OCF₃ G222(a), (b), and (c)S —I —H -tert-butyl G223(a), (b), and (c) S —I —H -iso-propyl G224(a),(b), and (c) O —H —Cl —H G225(a), (b), and (c) O —H —Br —H G226(a), (b),and (c) O —H —F —H G227(a), (b), and (c) O —H —CH₃ —H G228(a), (b), and(c) O —H —CF₃ —H G229(a), (b), and (c) O —H —OCH₃ —H G230(a), (b), and(c) O —H —OCH₂CH₃ —H G231(a), (b), and (c) O —H —OCF₃ —H G232(a), (b),and (c) O —H -tert-butyl —H G233(a), (b), and (c) O —H -iso-propyl —HG234(a), (b), and (c) O —H —CH₃ —CH₃ G235(a), (b), and (c) O —H —H —HG236(a), (b), and (c) O —H —H —Cl G237(a), (b), and (c) O —H —H —BrG238(a), (b), and (c) O —H —H —F G239(a), (b), and (c) O —H —H —CH₃G240(a), (b), and (c) O —H —H —CF₃ G241(a), (b), and (c) O —H —H —OCH₃G242(a), (b), and (c) O —H —H —OCH₂CH₃ G243(a), (b), and (c) O —H —H—OCF₃ G244(a), (b), and (c) O —H —H -tert-butyl G245(a), (b), and (c) O—H —H -iso-propyl G246(a), (b), and (c) O —Cl —Cl —H G247(a), (b), and(c) O —Cl —Br —H G248(a), (b), and (c) O —Cl —F —H G249(a), (b), and (c)O —Cl —CH₃ —H G250(a), (b), and (c) O —Cl —CF₃ —H G251(a), (b), and (c)O —Cl —OCH₃ —H G252(a), (b), and (c) O —Cl —OCH₂CH₃ —H G253(a), (b), and(c) O —Cl —OCF₃ —H G254(a), (b), and (c) O —Cl -tert-butyl —H G255(a),(b), and (c) O —Cl -iso-propyl —H G256(a), (b), and (c) O —Cl —CH₃ —CH₃G257(a), (b), and (c) O —Cl —H —H G258(a), (b), and (c) O —Cl —H —CH₃G259(a), (b), and (c) O —Cl —H —Cl G260(a), (b), and (c) O —Cl —H —BrG261(a), (b), and (c) O —Cl —H —F G262(a), (b), and (c) O —Cl —H —CF₃G263(a), (b), and (c) O —Cl —H —OCH₃ G264(a), (b), and (c) O —Cl —H—OCH₂CH₃ G265(a), (b), and (c) O —Cl —H —OCF₃ G266(a), (b), and (c) O—Cl —H -tert-butyl G267(a), (b), and (c) O —Cl —H -iso-propyl G268(a),(b), and (c) O —Cl —H —OCF₃ G269(a), (b), and (c) O —Cl —H -tert-butylG270(a), (b), and (c) O —Cl —H -iso-propyl G271(a), (b), and (c) O —CH₃—Cl —H G272(a), (b), and (c) O —CH₃ —Br —H G273(a), (b), and (c) O —CH₃—F —H G274(a), (b), and (c) O —CH₃ —CH₃ —H G275(a), (b), and (c) O —CH₃—CF₃ —H G276(a), (b), and (c) O —CH₃ —OCH₃ —H G277(a), (b), and (c) O—CH₃ —OCH₂CH₃ —H G278(a), (b), and (c) O —CH₃ —OCF₃ —H G279(a), (b), and(c) O —CH₃ -tert-butyl —H G280(a), (b), and (c) O —CH₃ -iso-propyl —HG281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ G282(a), (b), and (c) O —CH₃ —H—H G283(a), (b), and (c) O —CH₃ —H —Cl G284(a), (b), and (c) O —CH₃ —H—Br G285(a), (b), and (c) O —CH₃ —H —F G286(a), (b), and (c) O —CH₃ —H—CH₃ G287(a), (b), and (c) O —CH₃ —H —CF₃ G288(a), (b), and (c) O —CH₃—H —OCH₃ G289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ G290(a), (b), and (c)O —CH₃ —H —OCF₃ G291(a), (b), and (c) O —CH₃ —H -tert-butyl G292(a),(b), and (c) O —CH₃ —H -iso-propyl G293(a), (b), and (c) O —CF₃ —Cl —HG294(a), (b), and (c) O —CF₃ —Br —H G295(a), (b), and (c) O —CF₃ —F —HG296(a), (b), and (c) O —CF₃ —CH₃ —H G297(a), (b), and (c) O —CF₃ —CF₃—H G298(a), (b), and (c) O —CF₃ —OCH₃ —H G299(a), (b), and (c) O —CF₃—OCH₂CH₃ —H G300(a), (b), and (c) O —CF₃ —OCF₃ —H G301(a), (b), and (c)O —CF₃ -tert-butyl —H G302(a), (b), and (c) O —CF₃ -iso-propyl —HG303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ G304(a), (b), and (c) O —CF₃ —H—H G305(a), (b), and (c) O —CF₃ —H —Cl G306(a), (b), and (c) O —CF₃ —H—Br G307(a), (b), and (c) O —CF₃ —H —F G308(a), (b), and (c) O —CF₃ —H—CH₃ G309(a), (b), and (c) O —CF₃ —H —CF₃ G310(a), (b), and (c) O —CF₃—H —OCH₃ G311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ G312(a), (b), and (c)O —CF₃ —H —OCF₃ G313(a), (b), and (c) O —CF₃ —H -tert-butyl G314(a),(b), and (c) O —CF₃ —H -iso-propyl G315(a), (b), and (c) O —CHF₂ —Cl —HG316(a), (b), and (c) O —CHF₂ —Br —H G317(a), (b), and (c) O —CHF₂ —F —HG318(a), (b), and (c) O —CHF₂ —CH₃ —H G319(a), (b), and (c) O —CHF₂ —CF₃—H G320(a), (b), and (c) O —CHF₂ —OCH₃ —H G321(a), (b), and (c) O —CHF₂—OCH₂CH₃ —H G322(a), (b), and (c) O —CHF₂ —OCF₃ —H G323(a), (b), and (c)O —CHF₂ -tert-butyl —H G324(a), (b), and (c) O —CHF₂ -iso-propyl —HG325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ G326(a), (b), and (c) O —CHF₂ —H—H G327(a), (b), and (c) O —CHF₂ —H —Cl G328(a), (b), and (c) O —CHF₂ —H—Br G329(a), (b), and (c) O —CHF₂ —H —F G330(a), (b), and (c) O —CHF₂ —H—CH₃ G331(a), (b), and (c) O —CHF₂ —H —CF₃ G332(a), (b), and (c) O —CHF₂—H —OCH₃ G333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ G334(a), (b), and (c)O —CHF₂ —H —OCF₃ G335(a), (b), and (c) O —CHF₂ —H -tert-butyl G336(a),(b), and (c) O —CHF₂ —H -iso-propyl G337(a), (b), and (c) O —OH —Cl —HG338(a), (b), and (c) O —OH —Br —H G339(a), (b), and (c) O —OH —F —HG340(a), (b), and (c) O —OH —CH₃ —H G341(a), (b), and (c) O —OH —CF₃ —HG342(a), (b), and (c) O —OH —OCH₃ —H G343(a), (b), and (c) O —OH—OCH₂CH₃ —H G344(a), (b), and (c) O —OH —OCF₃ —H G345(a), (b), and (c) O—OH -tert-butyl —H G346(a), (b), and (c) O —OH -iso-propyl —H G347(a),(b), and (c) O —OH —CH₃ —CH₃ G348(a), (b), and (c) O —OH —H —H G349(a),(b), and (c) O —OH —H —Cl G350(a), (b), and (c) O —OH —H —Br G351(a),(b), and (c) O —OH —H —F G352(a), (b), and (c) O —OH —H —CH₃ G353(a),(b), and (c) O —OH —H —CF₃ G354(a), (b), and (c) O —OH —H —OCH₃ G355(a),(b), and (c) O —OH —H —OCH₂CH₃ G356(a), (b), and (c) O —OH —H —OCF₃G357(a), (b), and (c) O —OH —H -tert-butyl G358(a), (b), and (c) O —OH—H -iso-propyl G359(a), (b), and (c) O —NO₂ —Cl —H G360(a), (b), and (c)O —NO₂ —Br —H G361(a), (b), and (c) O —NO₂ —F —H G362(a), (b), and (c) O—NO₂ —CH₃ —H G363(a), (b), and (c) O —NO₂ —CF₃ —H G364(a), (b), and (c)O —NO₂ —OCH₃ —H G365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H G366(a), (b),and (c) O —NO₂ —OCF₃ —H G367(a), (b), and (c) O —NO₂ -tert-butyl —HG368(a), (b), and (c) O —NO₂ -iso-propyl —H G369(a), (b), and (c) O —NO₂—CH₃ —CH₃ G370(a), (b), and (c) O —NO₂ —H —H G371(a), (b), and (c) O—NO₂ —H —Cl G372(a), (b), and (c) O —NO₂ —H —Br G373(a), (b), and (c) O—NO₂ —H —F G374(a), (b), and (c) O —NO₂ —H —CH₃ G375(a), (b), and (c) O—NO₂ —H —CF₃ G376(a), (b), and (c) O —NO₂ —H —OCH₃ G377(a), (b), and (c)O —NO₂ —H —OCH₂CH₃ G378(a), (b), and (c) O —NO₂ —H —OCF₃ G379(a), (b),and (c) O —NO₂ —H -tert-butyl G380(a), (b), and (c) O —NO₂ —H-iso-propyl G381(a), (b), and (c) O —CN —Br —H G382(a), (b), and (c) O—CN —Cl —H G383(a), (b), and (c) O —CN —F —H G384(a), (b), and (c) O —CN—CH₃ —H G385(a), (b), and (c) O —CN —CF₃ —H G386(a), (b), and (c) O —CN—OCH₃ —H G387(a), (b), and (c) O —CN —OCH₂CH₃ —H G388(a), (b), and (c) O—CN —OCF₃ —H G389(a), (b), and (c) O —CN -tert-butyl —H G390(a), (b),and (c) O —CN -iso-propyl —H G391(a), (b), and (c) O —CN —CH₃ —CH₃G392(a), (b), and (c) O —CN —H —H G393(a), (b), and (c) O —CN —H —ClG394(a), (b), and (c) O —CN —H —Br G395(a), (b), and (c) O —CN —H —FG396(a), (b), and (c) O —CN —H —CH₃ G397(a), (b), and (c) O —CN —H —CF₃G398(a), (b), and (c) O —CN —H —OCH₃ G399(a), (b), and (c) O —CN —H—OCH₂CH₃ G400(a), (b), and (c) O —CN —H —OCF₃ G401(a), (b), and (c) O—CN —H -tert-butyl G402(a), (b), and (c) O —CN —H -iso-propyl G403(a),(b), and (c) O —Br —Br —H G404(a), (b), and (c) O —Br —Cl —H G405(a),(b), and (c) O —Br —F —H G406(a), (b), and (c) O —Br —CH₃ —H G407(a),(b), and (c) O —Br —CF₃ —H G408(a), (b), and (c) O —Br —OCH₃ —H G409(a),(b), and (c) O —Br —OCH₂CH₃ —H G410(a), (b), and (c) O —Br —OCF₃ —HG411(a), (b), and (c) O —Br -tert-butyl —H G412(a), (b), and (c) O —Br-iso-propyl —H G413(a), (b), and (c) O —Br —CH₃ —CH₃ G414(a), (b), and(c) O —Br —H —H G415(a), (b), and (c) O —Br —H —Cl G416(a), (b), and (c)O —Br —H —Br G417(a), (b), and (c) O —Br —H —F G418(a), (b), and (c) O—Br —H —CH₃ G419(a), (b), and (c) O —Br —H —CF₃ G420(a), (b), and (c) O—Br —H —OCH₃ G421(a), (b), and (c) O —Br —H —OCH₂CH₃ G422(a), (b), and(c) O —Br —H —OCF₃ G423(a), (b), and (c) O —Br —H -tert-butyl G424(a),(b), and (c) O —Br —H -iso-propyl G425(a), (b), and (c) O —I —Cl —HG426(a), (b), and (c) O —I —Br —H G427(a), (b), and (c) O —I —F —HG428(a), (b), and (c) O —I —CH₃ —H G429(a), (b), and (c) O —I —CF₃ —HG430(a), (b), and (c) O —I —OCH₃ —H G431(a), (b), and (c) O —I —OCH₂CH₃—H G432(a), (b), and (c) O —I —OCF₃ —H G433(a), (b), and (c) O —I-tert-butyl —H G434(a), (b), and (c) O —I -iso-propyl —H G435(a), (b),and (c) O —I —CH₃ —CH₃ G436(a), (b), and (c) O —I —H —H G437(a), (b),and (c) O —I —H —Cl G438(a), (b), and (c) O —I —H —Br G439(a), (b), and(c) O —I —H —F G440(a), (b), and (c) O —I —H —CH₃ G441(a), (b), and (c)O —I —H —CF₃ G442(a), (b), and (c) O —I —H —OCH₃ G443(a), (b), and (c) O—I —H —OCH₂CH₃ G444(a), (b), and (c) O —I —H —OCF₃ G445(a), (b), and (c)O —I —H -tert-butyl G446(a), (b), and (c) O —I —H -iso-propyl G447(a),(b), and (c) NH —H —Cl —H G448(a), (b), and (c) NH —H —Br —H G449(a),(b), and (c) NH —H —F —H G450(a), (b), and (c) NH —H —CH₃ —H G451(a),(b), and (c) NH —H —CF₃ —H G452(a), (b), and (c) NH —H —OCH₃ —H G453(a),(b), and (c) NH —H —OCH₂CH₃ —H G454(a), (b), and (c) NH —H —OCF₃ —HG455(a), (b), and (c) NH —H -tert-butyl —H G456(a), (b), and (c) NH —H-iso-propyl —H G457(a), (b), and (c) NH —H —CH₃ —CH₃ G458(a), (b), and(c) NH —H —H —H G459(a), (b), and (c) NH —H —H —Cl G460(a), (b), and (c)NH —H —H —Br G461(a), (b), and (c) NH —H —H —F G462(a), (b), and (c) NH—H —H —CH₃ G463(a), (b), and (c) NH —H —H —CF₃ G464(a), (b), and (c) NH—H —H —OCH₃ G465(a), (b), and (c) NH —H —H —OCH₂CH₃ G466(a), (b), and(c) NH —H —H —OCF₃ G467(a), (b), and (c) NH —H —H -tert-butyl G468(a),(b), and (c) NH —H —H -iso-propyl G469(a), (b), and (c) NH —Cl —Cl —HG470(a), (b), and (c) NH —Cl —Br —H G471(a), (b), and (c) NH —Cl —F —HG472(a), (b), and (c) NH —Cl —CH₃ —H G473(a), (b), and (c) NH —Cl —CF₃—H G474(a), (b), and (c) NH —Cl —OCH₃ —H G475(a), (b), and (c) NH —Cl—OCH₂CH₃ —H G476(a), (b), and (c) NH —Cl —OCF₃ —H G477(a), (b), and (c)NH —Cl -tert-butyl —H G478(a), (b), and (c) NH —Cl -iso-propyl —HG479(a), (b), and (c) NH —Cl —CH₃ —CH₃ G480(a), (b), and (c) NH —Cl —H—H G481(a), (b), and (c) NH —Cl —H —CH₃ G482(a), (b), and (c) NH —Cl —H—Cl G483(a), (b), and (c) NH —Cl —H —Br G484(a), (b), and (c) NH —Cl —H—F G485(a), (b), and (c) NH —Cl —H —CF₃ G486(a), (b), and (c) NH —Cl —H—OCH₃ G487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ G488(a), (b), and (c) NH—Cl —H —OCF₃ G489(a), (b), and (c) NH —Cl —H -tert-butyl G490(a), (b),and (c) NH —Cl —H -iso-propyl G491(a), (b), and (c) NH —Cl —H —OCF₃G492(a), (b), and (c) NH —Cl —H -tert-butyl G493(a), (b), and (c) NH —Cl—H -iso-propyl G494(a), (b), and (c) NH —CH₃ —Cl —H G495(a), (b), and(c) NH —CH₃ —Br —H G496(a), (b), and (c) NH —CH₃ —F —H G497(a), (b), and(c) NH —CH₃ —CH₃ —H G498(a), (b), and (c) NH —CH₃ —CF₃ —H G499(a), (b),and (c) NH —CH₃ —OCH₃ —H G500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —HG501(a), (b), and (c) NH —CH₃ —OCF₃ —H G502(a), (b), and (c) NH —CH₃-tert-butyl —H G503(a), (b), and (c) NH —CH₃ -iso-propyl —H G504(a),(b), and (c) NH —CH₃ —CH₃ —CH₃ G505(a), (b), and (c) NH —CH₃ —H —HG506(a), (b), and (c) NH —CH₃ —H —Cl G507(a), (b), and (c) NH —CH₃ —H—Br G508(a), (b), and (c) NH —CH₃ —H —F G509(a), (b), and (c) NH —CH₃ —H—CH₃ G510(a), (b), and (c) NH —CH₃ —H —CF₃ G511(a), (b), and (c) NH —CH₃—H —OCH₃ G512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ G513(a), (b), and (c)NH —CH₃ —H —OCF₃ G514(a), (b), and (c) NH —CH₃ —H -tert-butyl G515(a),(b), and (c) NH —CH₃ —H -iso-propyl G516(a), (b), and (c) NH —CF₃ —Cl —HG517(a), (b), and (c) NH —CF₃ —Br —H G518(a), (b), and (c) NH —CF₃ —F —HG519(a), (b), and (c) NH —CF₃ —CH₃ —H G520(a), (b), and (c) NH —CF₃ —CF₃—H G521(a), (b), and (c) NH —CF₃ —OCH₃ —H G522(a), (b), and (c) NH —CF₃—OCH₂CH₃ —H G523(a), (b), and (c) NH —CF₃ —OCF₃ —H G524(a), (b), and (c)NH —CF₃ -tert-butyl —H G525(a), (b), and (c) NH —CF₃ -iso-propyl —HG526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ G527(a), (b), and (c) NH —CF₃ —H—H G528(a), (b), and (c) NH —CF₃ —H —Cl G529(a), (b), and (c) NH —CF₃ —H—Br G530(a), (b), and (c) NH —CF₃ —H —F G531(a), (b), and (c) NH —CF₃ —H—CH₃ G532(a), (b), and (c) NH —CF₃ —H —CF₃ G533(a), (b), and (c) NH —CF₃—H —OCH₃ G534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ G535(a), (b), and (c)NH —CF₃ —H —OCF₃ G536(a), (b), and (c) NH —CF₃ —H -tert-butyl G537(a),(b), and (c) NH —CF₃ —H -iso-propyl G538(a), (b), and (c) NH —CHF₂ —Cl—H G539(a), (b), and (c) NH —CHF₂ —Br —H G540(a), (b), and (c) NH —CHF₂—F —H G541(a), (b), and (c) NH —CHF₂ —CH₃ —H G542(a), (b), and (c) NH—CHF₂ —CF₃ —H G543(a), (b), and (c) NH —CHF₂ —OCH₃ —H G544(a), (b), and(c) NH —CHF₂ —OCH₂CH₃ —H G545(a), (b), and (c) NH —CHF₂ —OCF₃ —HG546(a), (b), and (c) NH —CHF₂ -tert-butyl —H G547(a), (b), and (c) NH—CHF₂ -iso-propyl —H G548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ G549(a),(b), and (c) NH —CHF₂ —H —H G550(a), (b), and (c) NH —CHF₂ —H —ClG551(a), (b), and (c) NH —CHF₂ —H —Br G552(a), (b), and (c) NH —CHF₂ —H—F G553(a), (b), and (c) NH —CHF₂ —H —CH₃ G554(a), (b), and (c) NH —CHF₂—H —CF₃ G555(a), (b), and (c) NH —CHF₂ —H —OCH₃ G556(a), (b), and (c) NH—CHF₂ —H —OCH₂CH₃ G557(a), (b), and (c) NH —CHF₂ —H —OCF₃ G558(a), (b),and (c) NH —CHF₂ —H -tert-butyl G559(a), (b), and (c) NH —CHF₂ —H-iso-propyl G560(a), (b), and (c) NH —OH —Cl —H G561(a), (b), and (c) NH—OH —Br —H G562(a), (b), and (c) NH —OH —F —H G563(a), (b), and (c) NH—OH —CH₃ —H G564(a), (b), and (c) NH —OH —CF₃ —H G565(a), (b), and (c)NH —OH —OCH₃ —H G566(a), (b), and (c) NH —OH —OCH₂CH₃ —H G567(a), (b),and (c) NH —OH —OCF₃ —H G568(a), (b), and (c) NH —OH -tert-butyl —HG569(a), (b), and (c) NH —OH -iso-propyl —H G570(a), (b), and (c) NH —OH—CH₃ —CH₃ G571(a), (b), and (c) NH —OH —H —H G572(a), (b), and (c) NH—OH —H —Cl G573(a), (b), and (c) NH —OH —H —Br G574(a), (b), and (c) NH—OH —H —F G575(a), (b), and (c) NH —OH —H —CH₃ G576(a), (b), and (c) NH—OH —H —CF₃ G577(a), (b), and (c) NH —OH —H —OCH₃ G578(a), (b), and (c)NH —OH —H —OCH₂CH₃ G579(a), (b), and (c) NH —OH —H —OCF₃ G580(a), (b),and (c) NH —OH —H -tert-butyl G581(a), (b), and (c) NH —OH —H-iso-propyl G582(a), (b), and (c) NH —NO₂ —Cl —H G583(a), (b), and (c)NH —NO₂ —Br —H G584(a), (b), and (c) NH —NO₂ —F —H G585(a), (b), and (c)NH —NO₂ —CH₃ —H G586(a), (b), and (c) NH —NO₂ —CF₃ —H G587(a), (b), and(c) NH —NO₂ —OCH₃ —H G588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H G589(a),(b), and (c) NH —NO₂ —OCF₃ —H G590(a), (b), and (c) NH —NO₂ -tert-butyl—H G591(a), (b), and (c) NH —NO₂ -iso-propyl —H G592(a), (b), and (c) NH—NO₂ —CH₃ —CH₃ G593(a), (b), and (c) NH —NO₂ —H —H G594(a), (b), and (c)NH —NO₂ —H —Cl G595(a), (b), and (c) NH —NO₂ —H —Br G596(a), (b), and(c) NH —NO₂ —H —F G597(a), (b), and (c) NH —NO₂ —H —CH₃ G598(a), (b),and (c) NH —NO₂ —H —CF₃ G599(a), (b), and (c) NH —NO₂ —H —OCH₃ G600(a),(b), and (c) NH —NO₂ —H —OCH₂CH₃ G601(a), (b), and (c) NH —NO₂ —H —OCF₃G602(a), (b), and (c) NH —NO₂ —H -tert-butyl G603(a), (b), and (c) NH—NO₂ —H -iso-propyl G604(a), (b), and (c) NH —CN —Br —H G605(a), (b),and (c) NH —CN —Cl —H G606(a), (b), and (c) NH —CN —F —H G607(a), (b),and (c) NH —CN —CH₃ —H G608(a), (b), and (c) NH —CN —CF₃ —H G609(a),(b), and (c) NH —CN —OCH₃ —H G610(a), (b), and (c) NH —CN —OCH₂CH₃ —HG611(a), (b), and (c) NH —CN —OCF₃ —H G612(a), (b), and (c) NH —CN-tert-butyl —H G613(a), (b), and (c) NH —CN -iso-propyl —H G614(a), (b),and (c) NH —CN —CH₃ —CH₃ G615(a), (b), and (c) NH —CN —H —H G616(a),(b), and (c) NH —CN —H —Cl G617(a), (b), and (c) NH —CN —H —Br G618(a),(b), and (c) NH —CN —H —F G619(a), (b), and (c) NH —CN —H —CH₃ G620(a),(b), and (c) NH —CN —H —CF₃ G621(a), (b), and (c) NH —CN —H —OCH₃G622(a), (b), and (c) NH —CN —H —OCH₂CH₃ G623(a), (b), and (c) NH —CN —H—OCF₃ G624(a), (b), and (c) NH —CN —H -tert-butyl G625(a), (b), and (c)NH —CN —H -iso-propyl G626(a), (b), and (c) NH —Br —Br —H G627(a), (b),and (c) NH —Br —Cl —H G628(a), (b), and (c) NH —Br —F —H G629(a), (b),and (c) NH —Br —CH₃ —H G630(a), (b), and (c) NH —Br —CF₃ —H G631(a),(b), and (c) NH —Br —OCH₃ —H G632(a), (b), and (c) NH —Br —OCH₂CH₃ —HG633(a), (b), and (c) NH —Br —OCF₃ —H G634(a), (b), and (c) NH —Br-tert-butyl —H G635(a), (b), and (c) NH —Br -iso-propyl —H G636(a), (b),and (c) NH —Br —CH₃ —CH₃ G637(a), (b), and (c) NH —Br —H —H G638(a),(b), and (c) NH —Br —H —Cl G639(a), (b), and (c) NH —Br —H —Br G640(a),(b), and (c) NH —Br —H —F G641(a), (b), and (c) NH —Br —H —CH₃ G642(a),(b), and (c) NH —Br —H —CF₃ G643(a), (b), and (c) NH —Br —H —OCH₃G644(a), (b), and (c) NH —Br —H —OCH₂CH₃ G645(a), (b), and (c) NH —Br —H—OCF₃ G646(a), (b), and (c) NH —Br —H -tert-butyl G647(a), (b), and (c)NH —Br —H -iso-propyl G648(a), (b), and (c) NH —I —Cl —H G649(a), (b),and (c) NH —I —Br —H G650(a), (b), and (c) NH —I —F —H G651(a), (b), and(c) NH —I —CH₃ —H G652(a), (b), and (c) NH —I —CF₃ —H G653(a), (b), and(c) NH —I —OCH₃ —H G654(a), (b), and (c) NH —I —OCH₂CH₃ —H G655(a), (b),and (c) NH —I —OCF₃ —H G656(a), (b), and (c) NH —I -tert-butyl —HG657(a), (b), and (c) NH —I -iso-propyl —H G658(a), (b), and (c) NH —I—CH₃ —CH₃ G659(a), (b), and (c) NH —I —H —H G660(a), (b), and (c) NH —I—H —Cl G661(a), (b), and (c) NH —I —H —Br G662(a), (b), and (c) NH —I —H—F G663(a), (b), and (c) NH —I —H —CH₃ G664(a), (b), and (c) NH —I —H—CF₃ G665(a), (b), and (c) NH —I —H —OCH₃ G666(a), (b), and (c) NH —I —H—OCH₂CH₃ G667(a), (b), and (c) NH —I —H —OCF₃ G668(a), (b), and (c) NH—I —H -tert-butyl G669(a), (b), and (c) NH —I —H -iso-propyl (a) meansthat R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is—H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 8 (Ih)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁(R₈)_(a) (R₈)_(b) H01(a), (b), and (c) S —H —Cl —H H02(a), (b), and (c)S —H —Br —H H03(a), (b), and (c) S —H —F —H H04(a), (b), and (c) S —H—CH₃ —H H05(a), (b), and (c) S —H —CF₃ —H H06(a), (b), and (c) S —H—OCH₃ —H H07(a), (b), and (c) S —H —OCH₂CH₃ —H H08(a), (b), and (c) S —H—OCF₃ —H H09(a), (b), and (c) S —H -tert-butyl —H H10(a), (b), and (c) S—H -iso-propyl —H H11(a), (b), and (c) S —H —CH₃ —CH₃ H12(a), (b), and(c) S —H —H —H H13(a), (b), and (c) S —H —H —Cl H14(a), (b), and (c) S—H —H —Br H15(a), (b), and (c) S —H —H —F H16(a), (b), and (c) S —H —H—CH₃ H17(a), (b), and (c) S —H —H —CF₃ H18(a), (b), and (c) S —H —H—OCH₃ H19(a), (b), and (c) S —H —H —OCH₂CH₃ H20(a), (b), and (c) S —H —H—OCF₃ H21(a), (b), and (c) S —H —H -tert-butyl H22(a), (b), and (c) S —H—H -iso-propyl H23(a), (b), and (c) S —Cl —Cl —H H24(a), (b), and (c) S—Cl —Br —H H25(a), (b), and (c) S —Cl —F —H H26(a), (b), and (c) S —Cl—CH₃ —H H27(a), (b), and (c) S —Cl —CF₃ —H H28(a), (b), and (c) S —Cl—OCH₃ —H H29(a), (b), and (c) S —Cl —OCH₂CH₃ —H H30(a), (b), and (c) S—Cl —OCF₃ —H H31(a), (b), and (c) S —Cl -tert-butyl —H H32(a), (b), and(c) S —Cl -iso-propyl —H H33(a), (b), and (c) S —Cl —CH₃ —CH₃ H34(a),(b), and (c) S —Cl —H —H H35(a), (b), and (c) S —Cl —H —Cl H36(a), (b),and (c) S —Cl —H —Br H37(a), (b), and (c) S —Cl —H —F H38(a), (b), and(c) S —Cl —H —CH₃ H39(a), (b), and (c) S —Cl —H —CF₃ H40(a), (b), and(c) S —Cl —H —OCH₃ H41(a), (b), and (c) S —Cl —H —OCH₂CH₃ H42(a), (b),and (c) S —Cl —H —OCF₃ H43(a), (b), and (c) S —Cl —H -tert-butyl H44(a),(b), and (c) S —Cl —H -iso-propyl H45(a), (b), and (c) S —Cl —H —OCF₃H46(a), (b), and (c) S —Cl —H -tert-butyl H47(a), (b), and (c) S —Cl —H-iso-propyl H48(a), (b), and (c) S —CH₃ —Cl —H H49(a), (b), and (c) S—CH₃ —Br —H H50(a), (b), and (c) S —CH₃ —F —H H51(a), (b), and (c) S—CH₃ —CH₃ —H H52(a), (b), and (c) S —CH₃ —CF₃ —H H53(a), (b), and (c) S—CH₃ —OCH₃ —H H54(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H H55(a), (b), and(c) S —CH₃ —OCF₃ —H H56(a), (b), and (c) S —CH₃ -tert-butyl —H H57(a),(b), and (c) S —CH₃ -iso-propyl —H H58(a), (b), and (c) S —CH₃ —CH₃ —CH₃H59(a), (b), and (c) S —CH₃ —H —H H60(a), (b), and (c) S —CH₃ —H —ClH61(a), (b), and (c) S —CH₃ —H —Br H62(a), (b), and (c) S —CH₃ — —FH63(a), (b), and (c) S —CH₃ —H —CH₃ H64(a), (b), and (c) S —CH₃ —H —CF₃H65(a), (b), and (c) S —CH₃ —H —OCH₃ H66(a), (b), and (c) S —CH₃ —H—OCH₂CH₃ H67(a), (b), and (c) S —CH₃ —H —OCF₃ H68(a), (b), and (c) S—CH₃ —H -tert-butyl H69(a), (b), and (c) S —CH₃ —H -iso-propyl H70(a),(b), and (c) S —CF₃ —Cl —H H71(a), (b), and (c) S —CF₃ —Br —H H72(a),(b), and (c) S —CF₃ —F —H H73(a), (b), and (c) S —CF₃ —CH₃ —H H74(a),(b), and (c) S —CF₃ —CF₃ —H H75(a), (b), and (c) S —CF₃ —OCH₃ —H H76(a),(b), and (c) S —CF₃ —OCH₂CH₃ —H H77(a), (b), and (c) S —CF₃ —OCF₃ —HH78(a), (b), and (c) S —CF₃ -tert-butyl —H H79(a), (b), and (c) S —CF₃-iso-propyl —H H80(a), (b), and (c) S —CF₃ —CH₃ —CH₃ H81(a), (b), and(c) S —CF₃ —H —H H82(a), (b), and (c) S —CF₃ —H —Cl H83(a), (b), and (c)S —CF₃ —H —Br H84(a), (b), and (c) S —CF₃ —H —F H85(a), (b), and (c) S—CF₃ —H —CH₃ H86(a), (b), and (c) S —CF₃ —H —CF₃ H87(a), (b), and (c) S—CF₃ —H —OCH₃ H88(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ H89(a), (b), and(c) S —CF₃ —H —OCF₃ H90(a), (b), and (c) S —CF₃ —H -tert-butyl H91(a),(b), and (c) S —CF₃ —H -iso-propyl H92(a), (b), and (c) S —CHF₂ —Cl —HH93(a), (b), and (c) S —CHF₂ —Br —H H94(a), (b), and (c) S —CHF₂ —F —HH95(a), (b), and (c) S —CHF₂ —CH₃ —H H96(a), (b), and (c) S —CHF₂ —CF₃—H H97(a), (b), and (c) S —CHF₂ —OCH₃ —H H98(a), (b), and (c) S —CHF₂—OCH₂CH₃ —H H99(a), (b), and (c) S —CHF₂ —OCF₃ —H H100(a), (b), and (c)S —CHF₂ -tert-butyl —H H101(a), (b), and (c) S —CHF₂ -iso-propyl —HH102(a), (b), and (c) S —CHF₂ —CH₃ —CH₃ H103(a), (b), and (c) S —CHF₂ —H—H H104(a), (b), and (c) S —CHF₂ —H —Cl H105(a), (b), and (c) S —CHF₂ —H—Br H106(a), (b), and (c) S —CHF₂ —H —F H107(a), (b), and (c) S —CHF₂ —H—CH₃ H108(a), (b), and (c) S —CHF₂ —H —CF₃ H109(a), (b), and (c) S —CHF₂—H —OCH₃ H110(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ H111(a), (b), and (c)S —CHF₂ —H —OCF₃ H112(a), (b), and (c) S —CHF₂ —H -tert-butyl H113(a),(b), and (c) S —CHF₂ —H -iso-propyl H114(a), (b), and (c) S —OH —Cl —HH115(a), (b), and (c) S —OH —Br —H H116(a), (b), and (c) S —OH —F —HH117(a), (b), and (c) S —OH —CH₃ —H H118(a), (b), and (c) S —OH —CF₃ —HH119(a), (b), and (c) S —OH —OCH₃ —H H120(a), (b), and (c) S —OH—OCH₂CH₃ —H H121(a), (b), and (c) S —OH —OCF₃ —H H122(a), (b), and (c) S—OH -tert-butyl —H H123(a), (b), and (c) S —OH -iso-propyl —H H124(a),(b), and (c) S —OH —CH₃ —CH₃ H125(a), (b), and (c) S —OH —H —H H126(a),(b), and (c) S —OH —H —Cl H127(a), (b), and (c) S —OH —H —Br H128(a),(b), and (c) S —OH —H —F H129(a), (b), and (c) S —OH —H —CH₃ H130(a),(b), and (c) S —OH —H —CF₃ H131(a), (b), and (c) S —OH —H —OCH₃ H132(a),(b), and (c) S —OH —H —OCH₂CH₃ H133(a), (b), and (c) S —OH —H —OCF₃H134(a), (b), and (c) S —OH —H -tert-butyl H135(a), (b), and (c) S —OH—H -iso-propyl H136(a), (b), and (c) S —NO₂ —Cl —H H137(a), (b), and (c)S —NO₂ —Br —H H138(a), (b), and (c) S —NO₂ —F —H H139(a), (b), and (c) S—NO₂ —CH₃ —H H140(a), (b), and (c) S —NO₂ —CF₃ —H H141(a), (b), and (c)S —NO₂ —OCH₃ —H H142(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H H143(a), (b),and (c) S —NO₂ —OCF₃ —H H144(a), (b), and (c) S —NO₂ -tert-butyl —HH145(a), (b), and (c) S —NO₂ -iso-propyl —H H146(a), (b), and (c) S —NO₂—CH₃ —CH₃ H147(a), (b), and (c) S —NO₂ —H —H H148(a), (b), and (c) S—NO₂ —H —Cl H149(a), (b), and (c) S —NO₂ —H —Br H150(a), (b), and (c) S—NO₂ —H —F H151(a), (b), and (c) S —NO₂ —H —CH₃ H152(a), (b), and (c) S—NO₂ —H —CF₃ H153(a), (b), and (c) S —NO₂ —H —OCH₃ H154(a), (b), and (c)S —NO₂ —H —OCH₂CH₃ H155(a), (b), and (c) S —NO₂ —H —OCF₃ H156(a), (b),and (c) S —NO₂ —H -tert-butyl H157(a), (b), and (c) S —NO₂ —H-iso-propyl H158(a), (b), and (c) S —CN —Br —H H159(a), (b), and (c) S—CN —Cl —H H160(a), (b), and (c) S —CN —F —H H161(a), (b), and (c) S —CN—CH₃ —H H162(a), (b), and (c) S —CN —CF₃ —H H163(a), (b), and (c) S —CN—OCH₃ —H H164(a), (b), and (c) S —CN —OCH₂CH₃ —H H165(a), (b), and (c) S—CN —OCF₃ —H H166(a), (b), and (c) S —CN -tert-butyl —H H167(a), (b),and (c) S —CN -iso-propyl —H H168(a), (b), and (c) S —CN —CH₃ —CH₃H169(a), (b), and (c) S —CN —H —H H170(a), (b), and (c) S —CN —H —ClH171(a), (b), and (c) S —CN —H —Br H172(a), (b), and (c) S —CN —H —FH173(a), (b), and (c) S —CN —H —CH₃ H174(a), (b), and (c) S —CN —H —CF₃H175(a), (b), and (c) S —CN —H —OCH₃ H176(a), (b), and (c) S —CN —H—OCH₂CH₃ H177(a), (b), and (c) S —CN —H —OCF₃ H178(a), (b), and (c) S—CN —H -tert-butyl H179(a), (b), and (c) S —CN —H -iso-propyl H180(a),(b), and (c) S —Br —Br —H H181(a), (b), and (c) S —Br —Cl —H H182(a),(b), and (c) S —Br —F —H H183(a), (b), and (c) S —Br —CH₃ —H H184(a),(b), and (c) S —Br —CF₃ —H H185(a), (b), and (c) S —Br —OCH₃ —H H186(a),(b), and (c) S —Br —OCH₂CH₃ —H H187(a), (b), and (c) S —Br —OCF₃ —HH188(a), (b), and (c) S —Br -tert-butyl —H H189(a), (b), and (c) S —Br-iso-propyl —H H190(a), (b), and (c) S —Br —CH₃ —CH₃ H191(a), (b), and(c) S —Br —H —H H192(a), (b), and (c) S —Br —H —Cl H193(a), (b), and (c)S —Br —H —Br H194(a), (b), and (c) S —Br —H —F H195(a), (b), and (c) S—Br —H —CH₃ H196(a), (b), and (c) S —Br —H —CF₃ H197(a), (b), and (c) S—Br —H —OCH₃ H198(a), (b), and (c) S —Br —H —OCH₂CH₃ H199(a), (b), and(c) S —Br —H —OCF₃ H200(a), (b), and (c) S —Br —H -tert-butyl H201(a),(b), and (c) S —Br —H -iso-propyl H202(a), (b), and (c) S —I —Cl —HH203(a), (b), and (c) S —I —Br —H H204(a), (b), and (c) S —I —F —HH205(a), (b), and (c) S —I —CH₃ —H H206(a), (b), and (c) S —I —CF₃ —HH207(a), (b), and (c) S —I —OCH₃ —H H208(a), (b), and (c) S —I —OCH₂CH₃—H H209(a), (b), and (c) 5 —I —OCF₃ —H H210(a), (b), and (c) S —I-tert-butyl —H H211(a), (b), and (c) S —I -iso-propyl —H H212(a), (b),and (c) S —I —CH₃ —CH₃ H213(a), (b), and (c) S —I —H —H H214(a), (b),and (c) S —I —H —Cl H215(a), (b), and (c) S —I —H —Br H216(a), (b), and(c) S —I —H —F H217(a), (b), and (c) S —I —H —CH₃ H218(a), (b), and (c)S —I —H —CF₃ H219(a), (b), and (c) S —I —H —OCH₃ H220(a), (b), and (c) S—I —H —OCH₂CH₃ H221(a), (b), and (c) S —I —H —OCF₃ H222(a), (b), and (c)S —I —H -tert-butyl H223(a), (b), and (c) S —I —H -iso-propyl H224(a),(b), and (c) O —H —Cl —H H225(a), (b), and (c) O —H —Br —H H226(a), (b),and (c) O —H —F —H H227(a), (b), and (c) O —H —CH₃ —H H228(a), (b), and(c) O —H —CF₃ —H H229(a), (b), and (c) O —H —OCH₃ —H H230(a), (b), and(c) O —H —OCH₂CH₃ —H H231(a), (b), and (c) O —H —OCF₃ —H H232(a), (b),and (c) O —H -tert-butyl —H H233(a), (b), and (c) O —H -iso-propyl —HH234(a), (b), and (c) O —H —CH₃ —CH₃ H235(a), (b), and (c) O —H —H —HH236(a), (b), and (c) O —H —H —Cl H237(a), (b), and (c) O —H —H —BrH238(a), (b), and (c) O —H —H —F H239(a), (b), and (c) O —H —H —CH₃H240(a), (b), and (c) O —H —H —CF₃ H241(a), (b), and (c) O —H —H —OCH₃H242(a), (b), and (c) O —H —H —OCH₂CH₃ H243(a), (b), and (c) O —H —H—OCF₃ H244(a), (b), and (c) O —H —H -tert-butyl H245(a), (b), and (c) O—H —H -iso-propyl H246(a), (b), and (c) O —Cl —Cl —H H247(a), (b), and(c) O —Cl —Br —H H248(a), (b), and (c) O —Cl —F —H H249(a), (b), and (c)O —Cl —CH₃ —H H250(a), (b), and (c) O —Cl —CF₃ —H H251(a), (b), and (c)O —Cl —OCH₃ —H H252(a), (b), and (c) O —Cl —OCH₂CH₃ —H H253(a), (b), and(c) O —Cl —OCF₃ —H H254(a), (b), and (c) O —Cl -tert-butyl —H H255(a),(b), and (c) O —Cl -iso-propyl —H H256(a), (b), and (c) O —Cl —CH₃ —CH₃H257(a), (b), and (c) O —Cl —H —H H258(a), (b), and (c) O —Cl —H —CH₃H259(a), (b), and (c) O —Cl —H —Cl H260(a), (b), and (c) O —Cl —H —BrH261(a), (b), and (c) O —Cl —H —F H262(a), (b), and (c) O —Cl —H —CF₃H263(a), (b), and (c) O —Cl —H —OCH₃ H264(a), (b), and (c) O —Cl —H—OCH₂CH₃ H265(a), (b), and (c) O —Cl —H —OCF₃ H266(a), (b), and (c) O—Cl —H -tert-butyl H267(a), (b), and (c) O —Cl —H -iso-propyl H268(a),(b), and (c) O —Cl —H —OCF₃ H269(a), (b), and (c) O —Cl —H -tert-butylH270(a), (b), and (c) O —Cl —H -iso-propyl H271(a), (b), and (c) O —CH₃—Cl —H H272(a), (b), and (c) O —CH₃ —Br —H H273(a), (b), and (c) O —CH₃—F —H H274(a), (b), and (c) O —CH₃ —CH₃ —H H275(a), (b), and (c) O —CH₃—CF₃ —H H276(a), (b), and (c) O —CH₃ —OCH₃ —H H277(a), (b), and (c) O—CH₃ —OCH₂CH₃ —H H278(a), (b), and (c) O —CH₃ —OCF₃ —H H279(a), (b), and(c) O —CH₃ -tert-butyl —H H280(a), (b), and (c) O —CH₃ -iso-propyl —HH281(a), (b), and (c) O —CH₃ —CH₃ —CH₃ H282(a), (b), and (c) O —CH₃ —H—H H283(a), (b), and (c) O —CH₃ —H —Cl H284(a), (b), and (c) O —CH₃ —H—Br H285(a), (b), and (c) O —CH₃ —H —F H286(a), (b), and (c) O —CH₃ —H—CH₃ H287(a), (b), and (c) O —CH₃ —H —CF₃ H288(a), (b), and (c) O —CH₃—H —OCH₃ H289(a), (b), and (c) O —CH₃ —H —OCH₂CH₃ H290(a), (b), and (c)O —CH₃ —H —OCF₃ H291(a), (b), and (c) O —CH₃ —H -tert-butyl H292(a),(b), and (c) O —CH₃ —H -iso-propyl H293(a), (b), and (c) O —CF₃ —Cl —HH294(a), (b), and (c) O —CF₃ —Br —H H295(a), (b), and (c) O —CF₃ —F —HH296(a), (b), and (c) O —CF₃ —CH₃ —H H297(a), (b), and (c) O —CF₃ —CF₃—H H298(a), (b), and (c) O —CF₃ —OCH₃ —H H299(a), (b), and (c) O —CF₃—OCH₂CH₃ —H H300(a), (b), and (c) O —CF₃ —OCF₃ —H H301(a), (b), and (c)O —CF₃ -tert-butyl —H H302(a), (b), and (c) O —CF₃ -iso-propyl —HH303(a), (b), and (c) O —CF₃ —CH₃ —CH₃ H304(a), (b), and (c) O —CF₃ —H—H H305(a), (b), and (c) O —CF₃ —H —Cl H306(a), (b), and (c) O —CF₃ —H—Br H307(a), (b), and (c) O —CF₃ —H —F H308(a), (b), and (c) O —CF₃ —H—CH₃ H309(a), (b), and (c) O —CF₃ —H —CF₃ H310(a), (b), and (c) O —CF₃—H —OCH₃ H311(a), (b), and (c) O —CF₃ —H —OCH₂CH₃ H312(a), (b), and (c)O —CF₃ —H —OCF₃ H313(a), (b), and (c) O —CF₃ —H -tert-butyl H314(a),(b), and (c) O —CF₃ —H -iso-propyl H315(a), (b), and (c) O —CHF₂ —Cl —HH316(a), (b), and (c) O —CHF₂ —Br —H H317(a), (b), and (c) O —CHF₂ —F —HH318(a), (b), and (c) O —CHF₂ —CH₃ —H H319(a), (b), and (c) O —CHF₂ —CF₃—H H320(a), (b), and (c) O —CHF₂ —OCH₃ —H H321(a), (b), and (c) O —CHF₂—OCH₂CH₃ —H H322(a), (b), and (c) O —CHF₂ —OCF₃ —H H323(a), (b), and (c)O —CHF₂ -tert-butyl —H H324(a), (b), and (c) O —CHF₂ -iso-propyl —HH325(a), (b), and (c) O —CHF₂ —CH₃ —CH₃ H326(a), (b), and (c) O —CHF₂ —H—H H327(a), (b), and (c) O —CHF₂ —H —Cl H328(a), (b), and (c) O —CHF₂ —H—Br H329(a), (b), and (c) O —CHF₂ —H —F H330(a), (b), and (c) O —CHF₂ —H—CH₃ H331(a), (b), and (c) O —CHF₂ —H —CF₃ H332(a), (b), and (c) O —CHF₂—H —OCH₃ H333(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ H334(a), (b), and (c)O —CHF₂ —H —OCF₃ H335(a), (b), and (c) O —CHF₂ —H -tert-butyl H336(a),(b), and (c) O —CHF₂ —H -iso-propyl H337(a), (b), and (c) O —OH —Cl —HH338(a), (b), and (c) O —OH —Br —H H339(a), (b), and (c) O —OH —F —HH340(a), (b), and (c) O —OH —CH₃ —H H341(a), (b), and (c) O —OH —CF₃ —HH342(a), (b), and (c) O —OH —OCH₃ —H H343(a), (b), and (c) O —OH—OCH₂CH₃ —H H344(a), (b), and (c) O —OH —OCF₃ —H H345(a), (b), and (c) O—OH -tert-butyl —H H346(a), (b), and (c) O —OH -iso-propyl —H H347(a),(b), and (c) O —OH —CH₃ —CH₃ H348(a), (b), and (c) O —OH —H —H H349(a),(b), and (c) O —OH —H —Cl H350(a), (b), and (c) O —OH —H —Br H351(a),(b), and (c) O —OH —H —F H352(a), (b), and (c) O —OH —H —CH₃ H353(a),(b), and (c) O —OH —H —CF₃ H354(a), (b), and (c) O —OH —H —OCH₃ H355(a),(b), and (c) O —OH —H —OCH₂CH₃ H356(a), (b), and (c) O —OH —H —OCF₃H357(a), (b), and (c) O —OH —H -tert-butyl H358(a), (b), and (c) O —OH—H -iso-propyl H359(a), (b), and (c) O —NO₂ —Cl —H H360(a), (b), and (c)O —NO₂ —Br —H H361(a), (b), and (c) O —NO₂ —F —H H362(a), (b), and (c) O—NO₂ —CH₃ —H H363(a), (b), and (c) O —NO₂ —CF₃ —H H364(a), (b), and (c)O —NO₂ —OCH₃ —H H365(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H H366(a), (b),and (c) O —NO₂ —OCF₃ —H H367(a), (b), and (c) O —NO₂ -tert-butyl —HH368(a), (b), and (c) O —NO₂ -iso-propyl —H H369(a), (b), and (c) O —NO₂—CH₃ —CH₃ H370(a), (b), and (c) O —NO₂ —H —H H371(a), (b), and (c) O—NO₂ —H —Cl H372(a), (b), and (c) O —NO₂ —H —Br H373(a), (b), and (c) O—NO₂ —H —F H374(a), (b), and (c) O —NO₂ —H —CH₃ H375(a), (b), and (c) O—NO₂ —H —CF₃ H376(a), (b), and (c) O —NO₂ —H —OCH₃ H377(a), (b), and (c)O —NO₂ —H —OCH₂CH₃ H378(a), (b), and (c) O —NO₂ —H —OCF₃ H379(a), (b),and (c) O —NO₂ —H -tert-butyl H380(a), (b), and (c) O —NO₂ —H-iso-propyl H381(a), (b), and (c) O —CN —Br —H H382(a), (b), and (c) O—CN —Cl —H H383(a), (b), and (c) O —CN —F —H H384(a), (b), and (c) O —CN—CH₃ —H H385(a), (b), and (c) O —CN —CF₃ —H H386(a), (b), and (c) O —CN—OCH₃ —H H387(a), (b), and (c) O —CN —OCH₂CH₃ —H H388(a), (b), and (c) O—CN —OCF₃ —H H389(a), (b), and (c) O —CN -tert-butyl —H H390(a), (b),and (c) O —CN -iso-propyl —H H391(a), (b), and (c) O —CN —CH₃ —CH₃H392(a), (b), and (c) O —CN —H —H H393(a), (b), and (c) O —CN —H —ClH394(a), (b), and (c) O —CN —H —Br H395(a), (b), and (c) O —CN —H —FH396(a), (b), and (c) O —CN —H —CH₃ H397(a), (b), and (c) O —CN —H —CF₃H398(a), (b), and (c) O —CN —H —OCH₃ H399(a), (b), and (c) O —CN —H—OCH₂CH₃ H400(a), (b), and (c) O —CN —H —OCF₃ H401(a), (b), and (c) O—CN —H -tert-butyl H402(a), (b), and (c) O —CN —H -iso-propyl H403(a),(b), and (c) O —Br —Br —H H404(a), (b), and (c) O —Br —Cl —H H405(a),(b), and (c) O —Br —F —H H406(a), (b), and (c) O —Br —CH₃ —H H407(a),(b), and (c) O —Br —CF₃ —H H408(a), (b), and (c) O —Br —OCH₃ —H H409(a),(b), and (c) O —Br —OCH₂CH₃ —H H410(a), (b), and (c) O —Br —OCF₃ —HH411(a), (b), and (c) O —Br -tert-butyl —H H412(a), (b), and (c) O —Br-iso-propyl —H H413(a), (b), and (c) O —Br —CH₃ —CH₃ H414(a), (b), and(c) O —Br —H —H H415(a), (b), and (c) O —Br —H —Cl H416(a), (b), and (c)O —Br —H —Br H417(a), (b), and (c) O —Br —H —F H418(a), (b), and (c) O—Br —H —CH₃ H419(a), (b), and (c) O —Br —H —CF₃ H420(a), (b), and (c) O—Br —H —OCH₃ H421(a), (b), and (c) O —Br —H —OCH₂CH₃ H422(a), (b), and(c) O —Br —H —OCF₃ H423(a), (b), and (c) O —Br —H -tert-butyl H424(a),(b), and (c) O —Br —H -iso-propyl H425(a), (b), and (c) O —I —Cl —HH426(a), (b), and (c) O —I —Br —H H427(a), (b), and (c) O —I —F —HH428(a), (b), and (c) O —I —CH₃ —H H429(a), (b), and (c) O —I —CF₃ —HH430(a), (b), and (c) O —I —OCH₃ —H H431(a), (b), and (c) O —I —OCH₂CH₃—H H432(a), (b), and (c) O —I —OCF₃ —H H433(a), (b), and (c) O —I-tert-butyl —H H434(a), (b), and (c) O —I -iso-propyl —H H435(a), (b),and (c) O —I —CH₃ —CH₃ H436(a), (b), and (c) O —I —H —H H437(a), (b),and (c) O —I —H —Cl H438(a), (b), and (c) O —I —H —Br H439(a), (b), and(c) O —I —H —F H440(a), (b), and (c) O —I —H —CH₃ H441(a), (b), and (c)O —I —H —CF₃ H442(a), (b), and (c) O —I —H —OCH₃ H443(a), (b), and (c) O—I —H —OCH₂CH₃ H444(a), (b), and (c) O —I —H —OCF₃ H445(a), (b), and (c)O —I —H -tert-butyl H446(a), (b), and (c) O —I —H -iso-propyl H447(a),(b), and (c) NH —H —Cl —H H448(a), (b), and (c) NH —H —Br —H H449(a),(b), and (c) NH —H —F —H H450(a), (b), and (c) NH —H —CH₃ —H H451(a),(b), and (c) NH —H —CF₃ —H H452(a), (b), and (c) NH —H —OCH₃ —H H453(a),(b), and (c) NH —H —OCH₂CH₃ —H H454(a), (b), and (c) NH —H —OCF₃ —HH455(a), (b), and (c) NH —H -tert-butyl —H H456(a), (b), and (c) NH —H-iso-propyl —H H457(a), (b), and (c) NH —H —CH₃ —CH₃ H458(a), (b), and(c) NH —H —H —H H459(a), (b), and (c) NH —H —H —Cl H460(a), (b), and (c)NH —H —H —Br H461(a), (b), and (c) NH —H —H —F H462(a), (b), and (c) NH—H —H —CH₃ H463(a), (b), and (c) NH —H —H —CF₃ H464(a), (b), and (c) NH—H —H —OCH₃ H465(a), (b), and (c) NH —H —H —OCH₂CH₃ H466(a), (b), and(c) NH —H —H —OCF₃ H467(a), (b), and (c) NH —H —H -tert-butyl H468(a),(b), and (c) NH —H —H -iso-propyl H469(a), (b), and (c) NH —Cl —Cl —HH470(a), (b), and (c) NH —Cl —Br —H H471(a), (b), and (c) NH —Cl —F —HH472(a), (b), and (c) NH —Cl —CH₃ —H H473(a), (b), and (c) NH —Cl —CF₃—H H474(a), (b), and (c) NH —Cl —OCH₃ —H H475(a), (b), and (c) NH —Cl—OCH₂CH₃ —H H476(a), (b), and (c) NH —Cl —OCF₃ —H H477(a), (b), and (c)NH —Cl -tert-butyl —H H478(a), (b), and (c) NH —Cl -iso-propyl —HH479(a), (b), and (c) NH —Cl —CH₃ —CH₃ H480(a), (b), and (c) NH —Cl —H—H H481(a), (b), and (c) NH —Cl —H —CH₃ H482(a), (b), and (c) NH —Cl —H—Cl H483(a), (b), and (c) NH —Cl —H —Br H484(a), (b), and (c) NH —Cl —H—F H485(a), (b), and (c) NH —Cl —H —CF₃ H486(a), (b), and (c) NH —Cl —H—OCH₃ H487(a), (b), and (c) NH —Cl —H —OCH₂CH₃ H488(a), (b), and (c) NH—Cl —H —OCF₃ H489(a), (b), and (c) NH —Cl —H -tert-butyl H490(a), (b),and (c) NH —Cl —H -iso-propyl H491(a), (b), and (c) NH —Cl —H —OCF₃H492(a), (b), and (c) NH —Cl —H -tert-butyl H493(a), (b), and (c) NH —Cl—H -iso-propyl H494(a), (b), and (c) NH —CH₃ —Cl —H H495(a), (b), and(c) NH —CH₃ —Br —H H496(a), (b), and (c) NH —CH₃ —F —H H497(a), (b), and(c) NH —CH₃ —CH₃ —H H498(a), (b), and (c) NH —CH₃ —CF₃ —H H499(a), (b),and (c) NH —CH₃ —OCH₃ —H H500(a), (b), and (c) NH —CH₃ —OCH₂CH₃ —HH501(a), (b), and (c) NH —CH₃ —OCF₃ —H H502(a), (b), and (c) NH —CH₃-tert-butyl —H H503(a), (b), and (c) NH —CH₃ -iso-propyl —H H504(a),(b), and (c) NH —CH₃ —CH₃ —CH₃ H505(a), (b), and (c) NH —CH₃ —H —HH506(a), (b), and (c) NH —CH₃ —H —Cl H507(a), (b), and (c) NH —CH₃ —H—Br H508(a), (b), and (c) NH —CH₃ —H —F H509(a), (b), and (c) NH —CH₃ —H—CH₃ H510(a), (b), and (c) NH —CH₃ —H —CF₃ H511(a), (b), and (c) NH —CH₃—H —OCH₃ H512(a), (b), and (c) NH —CH₃ —H —OCH₂CH₃ H513(a), (b), and (c)NH —CH₃ —H —OCF₃ H514(a), (b), and (c) NH —CH₃ —H -tert-butyl H515(a),(b), and (c) NH —CH₃ —H -iso-propyl H516(a), (b), and (c) NH —CF₃ —Cl —HH517(a), (b), and (c) NH —CF₃ —Br —H H518(a), (b), and (c) NH —CF₃ —F —HH519(a), (b), and (c) NH —CF₃ —CH₃ —H H520(a), (b), and (c) NH —CF₃ —CF₃—H H521(a), (b), and (c) NH —CF₃ —OCH₃ —H H522(a), (b), and (c) NH —CF₃—OCH₂CH₃ —H H523(a), (b), and (c) NH —CF₃ —OCF₃ —H H524(a), (b), and (c)NH —CF₃ -tert-butyl —H H525(a), (b), and (c) NH —CF₃ -iso-propyl —HH526(a), (b), and (c) NH —CF₃ —CH₃ —CH₃ H527(a), (b), and (c) NH —CF₃ —H—H H528(a), (b), and (c) NH —CF₃ —H —Cl H529(a), (b), and (c) NH —CF₃ —H—Br H530(a), (b), and (c) NH —CF₃ —H —F H531(a), (b), and (c) NH —CF₃ —H—CH₃ H532(a), (b), and (c) NH —CF₃ —H —CF₃ H533(a), (b), and (c) NH —CF₃—H —OCH₃ H534(a), (b), and (c) NH —CF₃ —H —OCH₂CH₃ H535(a), (b), and (c)NH —CF₃ —H —OCF₃ H536(a), (b), and (c) NH —CF₃ —H -tert-butyl H537(a),(b), and (c) NH —CF₃ —H -iso-propyl H538(a), (b), and (c) NH —CHF₂ —Cl—H H539(a), (b), and (c) NH —CHF₂ —Br —H H540(a), (b), and (c) NH —CHF₂—F —H H541(a), (b), and (c) NH —CHF₂ —CH₃ —H H542(a), (b), and (c) NH—CHF₂ —CF₃ —H H543(a), (b), and (c) NH —CHF₂ —OCH₃ —H H544(a), (b), and(c) NH —CHF₂ —OCH₂CH₃ —H H545(a), (b), and (c) NH —CHF₂ —OCF₃ —HH546(a), (b), and (c) NH —CHF₂ -tert-butyl —H H547(a), (b), and (c) NH—CHF₂ -iso-propyl —H H548(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ H549(a),(b), and (c) NH —CHF₂ —H —H H550(a), (b), and (c) NH —CHF₂ —H —ClH551(a), (b), and (c) NH —CHF₂ —H —Br H552(a), (b), and (c) NH —CHF₂ —H—F H553(a), (b), and (c) NH —CHF₂ —H —CH₃ H554(a), (b), and (c) NH —CHF₂—H —CF₃ H555(a), (b), and (c) NH —CHF₂ —H —OCH₃ H556(a), (b), and (c) NH—CHF₂ —H —OCH₂CH₃ H557(a), (b), and (c) NH —CHF₂ —H —OCF₃ H558(a), (b),and (c) NH —CHF₂ —H -tert-butyl H559(a), (b), and (c) NH —CHF₂ —H-iso-propyl H560(a), (b), and (c) NH —OH —Cl —H H561(a), (b), and (c) NH—OH —Br —H H562(a), (b), and (c) NH —OH —F —H H563(a), (b), and (c) NH—OH —CH₃ —H H564(a), (b), and (c) NH —OH —CF₃ —H H565(a), (b), and (c)NH —OH —OCH₃ —H H566(a), (b), and (c) NH —OH —OCH₂CH₃ —H H567(a), (b),and (c) NH —OH —OCF₃ —H H568(a), (b), and (c) NH —OH -tert-butyl —HH569(a), (b), and (c) NH —OH -iso-propyl —H H570(a), (b), and (c) NH —OH—CH₃ —CH₃ H571(a), (b), and (c) NH —OH —H —H H572(a), (b), and (c) NH—OH —H —Cl H573(a), (b), and (c) NH —OH —H —Br H574(a), (b), and (c) NH—OH —H —F H575(a), (b), and (c) NH —OH —H —CH₃ H576(a), (b), and (c) NH—OH —H —CF₃ H577(a), (b), and (c) NH —OH —H —OCH₃ H578(a), (b), and (c)NH —OH —H —OCH₂CH₃ H579(a), (b), and (c) NH —OH —H —OCF₃ H580(a), (b),and (c) NH —OH —H -tert-butyl H581(a), (b), and (c) NH —OH —H-iso-propyl H582(a), (b), and (c) NH —NO₂ —Cl —H H583(a), (b), and (c)NH —NO₂ —Br —H H584(a), (b), and (c) NH —NO₂ —F —H H585(a), (b), and (c)NH —NO₂ —CH₃ —H H586(a), (b), and (c) NH —NO₂ —CF₃ —H H587(a), (b), and(c) NH —NO₂ —OCH₃ —H H588(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H H589(a),(b), and (c) NH —NO₂ —OCF₃ —H H590(a), (b), and (c) NH —NO₂ -tert-butyl—H H591(a), (b), and (c) NH —NO₂ -iso-propyl —H H592(a), (b), and (c) NH—NO₂ —CH₃ —CH₃ H593(a), (b), and (c) NH —NO₂ —H —H H594(a), (b), and (c)NH —NO₂ —H —Cl H595(a), (b), and (c) NH —NO₂ —H —Br H596(a), (b), and(c) NH —NO₂ —H —F H597(a), (b), and (c) NH —NO₂ —H —CH₃ H598(a), (b),and (c) NH —NO₂ —H —CF₃ H599(a), (b), and (c) NH —NO₂ —H —OCH₃ H600(a),(b), and (c) NH —NO₂ —H —OCH₂CH₃ H601(a), (b), and (c) NH —NO₂ —H —OCF₃H602(a), (b), and (c) NH —NO₂ —H -tert-butyl H603(a), (b), and (c) NH—NO₂ —H -iso-propyl H604(a), (b), and (c) NH —CN —Br —H H605(a), (b),and (c) NH —CN —Cl —H H606(a), (b), and (c) NH —CN —F —H H607(a), (b),and (c) NH —CN —CH₃ —H H608(a), (b), and (c) NH —CN —CF₃ —H H609(a),(b), and (c) NH —CN —OCH₃ —H H610(a), (b), and (c) NH —CN —OCH₂CH₃ —HH611(a), (b), and (c) NH —CN —OCF₃ —H H612(a), (b), and (c) NH —CN-tert-butyl —H H613(a), (b), and (c) NH —CN -iso-propyl —H H614(a), (b),and (c) NH —CN —CH₃ —CH₃ H615(a), (b), and (c) NH —CN —H —H H616(a),(b), and (c) NH —CN —H —Cl H617(a), (b), and (c) NH —CN —H —Br H618(a),(b), and (c) NH —CN —H —F H619(a), (b), and (c) NH —CN —H —CH₃ H620(a),(b), and (c) NH —CN —H —CF₃ H621(a), (b), and (c) NH —CN —H —OCH₃H622(a), (b), and (c) NH —CN —H —OCH₂CH₃ H623(a), (b), and (c) NH —CN —H—OCF₃ H624(a), (b), and (c) NH —CN —H -tert-butyl H625(a), (b), and (c)NH —CN —H -iso-propyl H626(a), (b), and (c) NH —Br —Br —H H627(a), (b),and (c) NH —Br —Cl —H H628(a), (b), and (c) NH —Br —F —H H629(a), (b),and (c) NH —Br —CH₃ —H H630(a), (b), and (c) NH —Br —CF₃ —H H631(a),(b), and (c) NH —Br —OCH₃ —H H632(a), (b), and (c) NH —Br —OCH₂CH₃ —HH633(a), (b), and (c) NH —Br —OCF₃ —H H634(a), (b), and (c) NH —Br-tert-butyl —H H635(a), (b), and (c) NH —Br -iso-propyl —H H636(a), (b),and (c) NH —Br —CH₃ —CH₃ H637(a), (b), and (c) NH —Br —H —H H638(a),(b), and (c) NH —Br —H —Cl H639(a), (b), and (c) NH —Br —H —Br H640(a),(b), and (c) NH —Br —H —F H641(a), (b), and (c) NH —Br —H —CH₃ H642(a),(b), and (c) NH —Br —H —CF₃ H643(a), (b), and (c) NH —Br —H —OCH₃H644(a), (b), and (c) NH —Br —H —OCH₂CH₃ H645(a), (b), and (c) NH —Br —H—OCF₃ H646(a), (b), and (c) NH —Br —H -tert-butyl H647(a), (b), and (c)NH —Br —H -iso-propyl H648(a), (b), and (c) NH —I —Cl —H H649(a), (b),and (c) NH —I —Br —H H650(a), (b), and (c) NH —I —F —H H651(a), (b), and(c) NH —I —CH₃ —H H652(a), (b), and (c) NH —I —CF₃ —H H653(a), (b), and(c) NH —I —OCH₃ —H H654(a), (b), and (c) NH —I —OCH₂CH₃ —H H655(a), (b),and (c) NH —I —OCF₃ —H H656(a), (b), and (c) NH —I -tert-butyl —HH657(a), (b), and (c) NH —I -iso-propyl —H H658(a), (b), and (c) NH —I—CH₃ —CH₃ H659(a), (b), and (c) NH —I —H —H H660(a), (b), and (c) NH —I—H —Cl H661(a), (b), and (c) NH —I —H —Br H662(a), (b), and (c) NH —I —H—F H663(a), (b), and (c) NH —I —H —CH₃ H664(a), (b), and (c) NH —I —H—CF₃ H665(a), (b), and (c) NH —I —H —OCH₃ H666(a), (b), and (c) NH —I —H—OCH₂CH₃ H667(a), (b), and (c) NH —I —H —OCF₃ H668(a), (b), and (c) NH—I —H -tert-butyl H669(a), (b), and (c) NH —I —H -iso-propyl (a) meansthat R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is—H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 9 (IIa)

and pharmaceutically acceptable salts thereof, where: Compound Y R₁(R₈)_(a) (R₈)_(b) I01(a), (b), and (c) S —Cl —Cl —H I02(a), (b), and (c)S —Cl —Br —H I03(a), (b), and (c) S —Cl —F —H I04(a), (b), and (c) S —Cl—CH₃ —H I05(a), (b), and (c) S —Cl —CF₃ —H I06(a), (b), and (c) S —Cl—OCH₃ —H I07(a), (b), and (c) S —Cl —OCH₂CH₃ —H I08(a), (b), and (c) S—Cl —OCF₃ —H I09(a), (b), and (c) S —Cl -tert-butyl —H I10(a), (b), and(c) S —Cl -iso-propyl —H I11(a), (b), and (c) S —Cl —CH₃ —CH₃ I12(a),(b), and (c) S —Cl —H —H I13(a), (b), and (c) S —Cl —H —Cl I14(a), (b),and (c) S —Cl —H —Br I15(a), (b), and (c) S —Cl —H —F I16(a), (b), and(c) S —Cl —H —CH₃ I17(a), (b), and (c) S —Cl —H —CF₃ I18(a), (b), and(c) S —Cl —H —OCH₃ I19(a), (b), and (c) S —Cl —H —OCH₂CH₃ I20(a), (b),and (c) S —Cl —H —OCF₃ I21(a), (b), and (c) S —Cl —H -tert-butyl I22(a),(b), and (c) S —Cl —H -iso-propyl I23(a), (b), and (c) S —Cl —H —OCF₃I24(a), (b), and (c) S —Cl —H -tert-butyl I25(a), (b), and (c) S —Cl —H-iso-propyl I26(a), (b), and (c) S —CH₃ —Cl —H I27(a), (b), and (c) S—CH₃ —Br —H I28(a), (b), and (c) S —CH₃ —F —H I29(a), (b), and (c) S—CH₃ —CH₃ —H I30(a), (b), and (c) S —CH₃ —CF₃ —H I31(a), (b), and (c) S—CH₃ —OCH₃ —H I32(a), (b), and (c) S —CH₃ —OCH₂CH₃ —H I33(a), (b), and(c) S —CH₃ —OCF₃ —H I34(a), (b), and (c) S —CH₃ -tert-butyl —H I35(a),(b), and (c) S —CH₃ -iso-propyl —H I36(a), (b), and (c) S —CH₃ —CH₃ —CH₃I37(a), (b), and (c) S —CH₃ —H —H I38(a), (b), and (c) S —CH₃ —H —ClI39(a), (b), and (c) S —CH₃ —H —Br I40(a), (b), and (c) S —CH₃ —H —FI41(a), (b), and (c) S —CH₃ —H —CH₃ I42(a), (b), and (c) S —CH₃ —H —CF₃I43(a), (b), and (c) S —CH₃ —H —OCH₃ I44(a), (b), and (c) S —CH₃ —H—OCH₂CH₃ I45(a), (b), and (c) S —CH₃ —H —OCF₃ I46(a), (b), and (c) S—CH₃ —H -tert-butyl I47(a), (b), and (c) S —CH₃ —H -iso-propyl I48(a),(b), and (c) S —CF₃ —Cl —H I49(a), (b), and (c) S —CF₃ —Br —H I50(a),(b), and (c) S —CF₃ —F —H I51(a), (b), and (c) S —CF₃ —CH₃ —H I52(a),(b), and (c) S —CF₃ —CF₃ —H I53(a), (b), and (c) S —CF₃ —OCH₃ —H I54(a),(b), and (c) S —CF₃ —OCH₂CH₃ —H I55(a), (b), and (c) S —CF₃ —OCF₃ —HI56(a), (b), and (c) S —CF₃ -tert-butyl —H I57(a), (b), and (c) S —CF₃-iso-propyl —H I58(a), (b), and (c) S —CF₃ —CH₃ —CH₃ I59(a), (b), and(c) S —CF₃ —H —H I60(a), (b), and (c) S —CF₃ —H —Cl I61(a), (b), and (c)S —CF₃ —H —Br I62(a), (b), and (c) S —CF₃ —H —F I63(a), (b), and (c) S—CF₃ —H —CH₃ I64(a), (b), and (c) S —CF₃ —H —CF₃ I65(a), (b), and (c) S—CF₃ —H —OCH₃ I66(a), (b), and (c) S —CF₃ —H —OCH₂CH₃ I67(a), (b), and(c) S —CF₃ —H —OCF₃ I68(a), (b), and (c) S —CF₃ —H -tert-butyl I69(a),(b), and (c) S —CF₃ —H -iso-propyl I70(a), (b), and (c) S —CHF₂ —Cl —HI71(a), (b), and (c) S —CHF₂ —Br —H I72(a), (b), and (c) S —CHF₂ —F —HI73(a), (b), and (c) S —CHF₂ —CH₃ —H I74(a), (b), and (c) S —CHF₂ —CF₃—H I75(a), (b), and (c) S —CHF₂ —OCH₃ —H I76(a), (b), and (c) S —CHF₂—OCH₂CH₃ —H I77(a), (b), and (c) S —CHF₂ —OCF₃ —H I78(a), (b), and (c) S—CHF₂ -tert-butyl —H I79(a), (b), and (c) S —CHF₂ -iso-propyl —H I80(a),(b), and (c) S —CHF₂ —CH₃ —CH₃ I81(a), (b), and (c) S —CHF₂ —H —HI82(a), (b), and (c) S —CHF₂ —H —Cl I83(a), (b), and (c) S —CHF₂ —H —BrI84(a), (b), and (c) S —CHF₂ —H —F I85(a), (b), and (c) S —CHF₂ —H —CH₃I86(a), (b), and (c) S —CHF₂ —H —CF₃ I87(a), (b), and (c) S —CHF₂ —H—OCH₃ I88(a), (b), and (c) S —CHF₂ —H —OCH₂CH₃ I89(a), (b), and (c) S—CHF₂ —H —OCF₃ I90(a), (b), and (c) S —CHF₂ —H -tert-butyl I91(a), (b),and (c) S —CHF₂ —H -iso-propyl I92(a), (b), and (c) S —OH —Cl —H I93(a),(b), and (c) S —OH —Br —H I94(a), (b), and (c) S —OH —F —H I95(a), (b),and (c) S —OH —CH₃ —H I96(a), (b), and (c) S —OH —CF₃ —H I97(a), (b),and (c) S —OH —OCH₃ —H I98(a), (b), and (c) S —OH —OCH₂CH₃ —H I99(a),(b), and (c) S —OH —OCF₃ —H I100(a), (b), and (c) S —OH -tert-butyl —HI101(a), (b), and (c) S —OH -iso-propyl —H I102(a), (b), and (c) S —OH—CH₃ —CH₃ I103(a), (b), and (c) S —OH —H —H I104(a), (b), and (c) S —OH—H —Cl I105(a), (b), and (c) S —OH —H —Br I106(a), (b), and (c) S —OH —H—F I107(a), (b), and (c) S —OH —H —CH₃ I108(a), (b), and (c) S —OH —H—CF₃ I109(a), (b), and (c) S —OH —H —OCH₃ I110(a), (b), and (c) S —OH —H—OCH₂CH₃ I111(a), (b), and (c) S —OH —H —OCF₃ I112(a), (b), and (c) S—OH —H -tert-butyl I113(a), (b), and (c) S —OH —H -iso-propyl I114(a),(b), and (c) S —NO₂ —Cl —H I115(a), (b), and (c) S —NO₂ —Br —H I116(a),(b), and (c) S —NO₂ —F —H I117(a), (b), and (c) S —NO₂ —CH₃ —H I118(a),(b), and (c) S —NO₂ —CF₃ —H I119(a), (b), and (c) S —NO₂ —OCH₃ —HI120(a), (b), and (c) S —NO₂ —OCH₂CH₃ —H I121(a), (b), and (c) S —NO₂—OCF₃ —H I122(a), (b), and (c) S —NO₂ -tert-butyl —H I123(a), (b), and(c) S —NO₂ -iso-propyl —H I124(a), (b), and (c) S —NO₂ —CH₃ —CH₃I125(a), (b), and (c) S —NO₂ —H —H I126(a), (b), and (c) S —NO₂ —H —ClI127(a), (b), and (c) S —NO₂ —H —Br I128(a), (b), and (c) S —NO₂ —H —FI129(a), (b), and (c) S —NO₂ —H —CH₃ I130(a), (b), and (c) S —NO₂ —H—CF₃ I131(a), (b), and (c) S —NO₂ —H —OCH₃ I132(a), (b), and (c) S —NO₂—H —OCH₂CH₃ I133(a), (b), and (c) S —NO₂ —H —OCF₃ I134(a), (b), and (c)S —NO₂ —H -tert-butyl I135(a), (b), and (c) S —NO₂ —H -iso-propylI136(a), (b), and (c) S —CN —Br —H I137(a), (b), and (c) S —CN —Cl —HI138(a), (b), and (c) S —CN —F —H I139(a), (b), and (c) S —CN —CH₃ —HI140(a), (b), and (c) S —CN —CF₃ —H I141(a), (b), and (c) S —CN —OCH₃ —HI142(a), (b), and (c) S —CN —OCH₂CH₃ —H I143(a), (b), and (c) S —CN—OCF₃ —H I144(a), (b), and (c) S —CN -tert-butyl —H I145(a), (b), and(c) S —CN -iso-propyl —H I146(a), (b), and (c) S —CN —CH₃ —CH₃ I147(a),(b), and (c) S —CN —H —H I148(a), (b), and (c) S —CN —H —Cl I149(a),(b), and (c) S —CN —H —Br I150(a), (b), and (c) S —CN —H —F I151(a),(b), and (c) S —CN —H —CH₃ I152(a), (b), and (c) S —CN —H —CF₃ I153(a),(b), and (c) S —CN —H —OCH₃ I154(a), (b), and (c) S —CN —H —OCH₂CH₃I155(a), (b), and (c) S —CN —H —OCF₃ I156(a), (b), and (c) S —CN —H-tert-butyl I157(a), (b), and (c) S —CN —H -iso-propyl I158(a), (b), and(c) S —Br —Br —H I159(a), (b), and (c) S —Br —Cl —H I160(a), (b), and(c) S —Br —F —H I161(a), (b), and (c) S —Br —CH₃ —H I162(a), (b), and(c) S —Br —CF₃ —H I163(a), (b), and (c) S —Br —OCH₃ —H I164(a), (b), and(c) S —Br —OCH₂CH₃ —H I165(a), (b), and (c) S —Br —OCF₃ —H I166(a), (b),and (c) S —Br -tert-butyl —H I167(a), (b), and (c) S —Br -iso-propyl —HI168(a), (b), and (c) S —Br —CH₃ —CH₃ I169(a), (b), and (c) S —Br —H —HI170(a), (b), and (c) S —Br —H —Cl I171(a), (b), and (c) S —Br —H —BrI172(a), (b), and (c) S —Br —H —F I173(a), (b), and (c) S —Br —H —CH₃I174(a), (b), and (c) S —Br —H —CF₃ I175(a), (b), and (c) S —Br —H —OCH₃I176(a), (b), and (c) S —Br —H —OCH₂CH₃ I177(a), (b), and (c) S —Br —H—OCF₃ I178(a), (b), and (c) S —Br —H -tert-butyl I179(a), (b), and (c) S—Br —H -iso-propyl I180(a), (b), and (c) S —I —Cl —H I181(a), (b), and(c) S —I —Br —H I182(a), (b), and (c) S —I —F —H I183(a), (b), and (c) S—I —CH₃ —H I184(a), (b), and (c) S —I —CF₃ —H I185(a), (b), and (c) S —I—OCH₃ —H I186(a), (b), and (c) S —I —OCH₂CH₃ —H I187(a), (b), and (c) S—I —OCF₃ —H I188(a), (b), and (c) S —I -tert-butyl —H I189(a), (b), and(c) S —I -iso-propyl —H I190(a), (b), and (c) S —I —CH₃ —CH₃ I191(a),(b), and (c) S —I —H —H I192(a), (b), and (c) S —I —H —Cl I193(a), (b),and (c) S —I —H —Br I194(a), (b), and (c) S —I —H —F I195(a), (b), and(c) S —I —H —CH₃ I196(a), (b), and (c) S —I —H —CF₃ I197(a), (b), and(c) S —I —H —OCH₃ I198(a), (b), and (c) S —I —H —OCH₂CH₃ I199(a), (b),and (c) S —I —H —OCF₃ I200(a), (b), and (c) S —I —H -tert-butyl I201(a),(b), and (c) S —I —H -iso-propyl I202(a), (b), and (c) O —Cl —Cl —HI203(a), (b), and (c) O —Cl —Br —H I204(a), (b), and (c) O —Cl —F —HI205(a), (b), and (c) O —Cl —CH₃ —H I206(a), (b), and (c) O —Cl —CF₃ —HI207(a), (b), and (c) O —Cl —OCH₃ —H I208(a), (b), and (c) O —Cl—OCH₂CH₃ —H I209(a), (b), and (c) O —Cl —OCF₃ —H I210(a), (b), and (c) O—Cl -tert-butyl —H I211(a), (b), and (c) O —Cl -iso-propyl —H I212(a),(b), and (c) O —Cl —CH₃ —CH₃ I213(a), (b), and (c) O —Cl —H —H I214(a),(b), and (c) O —Cl —H —CH₃ I215(a), (b), and (c) O —Cl —H —Cl I216(a),(b), and (c) O —Cl —H —Br I217(a), (b), and (c) O —Cl —H —F I218(a),(b), and (c) O —Cl —H —CF₃ I219(a), (b), and (c) O —Cl —H —OCH₃ I220(a),(b), and (c) O —Cl —H —OCH₂CH₃ I221(a), (b), and (c) O —Cl —H —OCF₃I222(a), (b), and (c) O —Cl —H -tert-butyl I223(a), (b), and (c) O —Cl—H -iso-propyl I224(a), (b), and (c) O —Cl —H —OCF₃ I225(a), (b), and(c) O —Cl —H -tert-butyl I226(a), (b), and (c) O —Cl —H -iso-propylI227(a), (b), and (c) O —CH₃ —Cl —H I228(a), (b), and (c) O —CH₃ —Br —HI229(a), (b), and (c) O —CH₃ —F —H I230(a), (b), and (c) O —CH₃ —CH₃ —HI231(a), (b), and (c) O —CH₃ —CF₃ —H I232(a), (b), and (c) O —CH₃ —OCH₃—H I233(a), (b), and (c) O —CH₃ —OCH₂CH₃ —H I234(a), (b), and (c) O —CH₃—OCF₃ —H I235(a), (b), and (c) O —CH₃ -tert-butyl —H I236(a), (b), and(c) O —CH₃ -iso-propyl —H I237(a), (b), and (c) O —CH₃ —CH₃ —CH₃I238(a), (b), and (c) O —CH₃ —H —H I239(a), (b), and (c) O —CH₃ —H —ClI240(a), (b), and (c) O —CH₃ —H —Br I241(a), (b), and (c) O —CH₃ —H —FI242(a), (b), and (c) O —CH₃ —H —CH₃ I243(a), (b), and (c) O —CH₃ —H—CF₃ I244(a), (b), and (c) O —CH₃ —H —OCH₃ I245(a), (b), and (c) O —CH₃—H —OCH₂CH₃ I246(a), (b), and (c) O —CH₃ —H —OCF₃ I247(a), (b), and (c)O —CH₃ —H -tert-butyl I248(a), (b), and (c) O —CH₃ —H -iso-propylI249(a), (b), and (c) O —CF₃ —Cl —H I250(a), (b), and (c) O —CF₃ —Br —HI251(a), (b), and (c) O —CF₃ —F —H I252(a), (b), and (c) O —CF₃ —CH₃ —HI253(a), (b), and (c) O —CF₃ —CF₃ —H I254(a), (b), and (c) O —CF₃ —OCH₃—H I255(a), (b), and (c) O —CF₃ —OCH₂CH₃ —H I256(a), (b), and (c) O —CF₃—OCF₃ —H I257(a), (b), and (c) O —CF₃ -tert-butyl —H I258(a), (b), and(c) O —CF₃ -iso-propyl —H I259(a), (b), and (c) O —CF₃ —CH₃ —CH₃I260(a), (b), and (c) O —CF₃ —H —H I261(a), (b), and (c) O —CF₃ —H —ClI262(a), (b), and (c) O —CF₃ —H —Br I263(a), (b), and (c) O —CF₃ —H —FI264(a), (b), and (c) O —CF₃ —H —CH₃ I265(a), (b), and (c) O —CF₃ —H—CF₃ I266(a), (b), and (c) O —CF₃ —H —OCH₃ I267(a), (b), and (c) O —CF₃—H —OCH₂CH₃ I268(a), (b), and (c) O —CF₃ —H —OCF₃ I269(a), (b), and (c)O —CF₃ —H -tert-butyl I270(a), (b), and (c) O —CF₃ —H -iso-propylI271(a), (b), and (c) O —CHF₂ —Cl —H I272(a), (b), and (c) O —CHF₂ —Br—H I273(a), (b), and (c) O —CHF₂ —F —H I274(a), (b), and (c) O —CHF₂—CH₃ —H I275(a), (b), and (c) O —CHF₂ —CF₃ —H I276(a), (b), and (c) O—CHF₂ —OCH₃ —H I277(a), (b), and (c) O —CHF₂ —OCH₂CH₃ —H I278(a), (b),and (c) O —CHF₂ —OCF₃ —H I279(a), (b), and (c) O —CHF₂ -tert-butyl —HI280(a), (b), and (c) O —CHF₂ -iso-propyl —H I281(a), (b), and (c) O—CHF₂ —CH₃ —CH₃ I282(a), (b), and (c) O —CHF₂ —H —H I283(a), (b), and(c) O —CHF₂ —H —Cl I284(a), (b), and (c) O —CHF₂ —H —Br I285(a), (b),and (c) O —CHF₂ —H —F I286(a), (b), and (c) O —CHF₂ —H —CH₃ I287(a),(b), and (c) O —CHF₂ —H —CF₃ I288(a), (b), and (c) O —CHF₂ —H —OCH₃I289(a), (b), and (c) O —CHF₂ —H —OCH₂CH₃ I290(a), (b), and (c) O —CHF₂—H —OCF₃ I291(a), (b), and (c) O —CHF₂ —H -tert-butyl I292(a), (b), and(c) O —CHF₂ —H -iso-propyl I293(a), (b), and (c) O —OH —Cl —H I294(a),(b), and (c) O —OH —Br —H I295(a), (b), and (c) O —OH —F —H I296(a),(b), and (c) O —OH —CH₃ —H I297(a), (b), and (c) O —OH —CF₃ —H I298(a),(b), and (c) O —OH —OCH₃ —H I299(a), (b), and (c) O —OH —OCH₂CH₃ —HI300(a), (b), and (c) O —OH —OCF₃ —H I301(a), (b), and (c) O —OH-tert-butyl —H I302(a), (b), and (c) O —OH -iso-propyl —H I303(a), (b),and (c) O —OH —CH₃ —CH₃ I304(a), (b), and (c) O —OH —H —H I305(a), (b),and (c) O —OH —H —Cl I306(a), (b), and (c) O —OH —H —Br I307(a), (b),and (c) O —OH —H —F I308(a), (b), and (c) O —OH —H —CH₃ I309(a), (b),and (c) O —OH —H —CF₃ I310(a), (b), and (c) O —OH —H —OCH₃ I311(a), (b),and (c) O —OH —H —OCH₂CH₃ I312(a), (b), and (c) O —OH —H —OCF₃ I313(a),(b), and (c) O —OH —H -tert-butyl I314(a), (b), and (c) O —OH —H-iso-propyl I315(a), (b), and (c) O —NO₂ —Cl —H I316(a), (b), and (c) O—NO₂ —Br —H I317(a), (b), and (c) O —NO₂ —F —H I318(a), (b), and (c) O—NO₂ —CH₃ —H I319(a), (b), and (c) O —NO₂ —CF₃ —H I320(a), (b), and (c)O —NO₂ —OCH₃ —H I321(a), (b), and (c) O —NO₂ —OCH₂CH₃ —H I322(a), (b),and (c) O —NO₂ —OCF₃ —H I323(a), (b), and (c) O —NO₂ -tert-butyl —HI324(a), (b), and (c) O —NO₂ -iso-propyl —H I325(a), (b), and (c) O —NO₂—CH₃ —CH₃ I326(a), (b), and (c) O —NO₂ —H —H I327(a), (b), and (c) O—NO₂ —H —Cl I328(a), (b), and (c) O —NO₂ —H —Br I329(a), (b), and (c) O—NO₂ —H —F I330(a), (b), and (c) O —NO₂ —H —CH₃ I331(a), (b), and (c) O—NO₂ —H —CF₃ I332(a), (b), and (c) O —NO₂ —H —OCH₃ I333(a), (b), and (c)O —NO₂ —H —OCH₂CH₃ I334(a), (b), and (c) O —NO₂ —H —OCF₃ I335(a), (b),and (c) O —NO₂ —H -tert-butyl I336(a), (b), and (c) O —NO₂ —H-iso-propyl I337(a), (b), and (c) O —CN —Br —H I338(a), (b), and (c) O—CN —Cl —H I339(a), (b), and (c) O —CN —F —H I340(a), (b), and (c) O —CN—CH₃ —H I341(a), (b), and (c) O —CN —CF₃ —H I342(a), (b), and (c) O —CN—OCH₃ —H I343(a), (b), and (c) O —CN —OCH₂CH₃ —H I344(a), (b), and (c) O—CN —OCF₃ —H I345(a), (b), and (c) O —CN -tert-butyl —H I346(a), (b),and (c) O —CN -iso-propyl —H I347(a), (b), and (c) O —CN —CH₃ —CH₃I348(a), (b), and (c) O —CN —H —H I349(a), (b), and (c) O —CN —H —ClI350(a), (b), and (c) O —CN —H —Br I351(a), (b), and (c) O —CN —H —FI352(a), (b), and (c) O —CN —H —CH₃ I353(a), (b), and (c) O —CN —H —CF₃I354(a), (b), and (c) O —CN —H —OCH₃ I355(a), (b), and (c) O —CN —H—OCH₂CH₃ I356(a), (b), and (c) O —CN —H —OCF₃ I357(a), (b), and (c) O—CN —H -tert-butyl I358(a), (b), and (c) O —CN —H -iso-propyl I359(a),(b), and (c) O —Br —Br —H I360(a), (b), and (c) O —Br —Cl —H I361(a),(b), and (c) O —Br —F —H I362(a), (b), and (c) O —Br —CH₃ —H I363(a),(b), and (c) O —Br —CF₃ —H I364(a), (b), and (c) O —Br —OCH₃ —H I365(a),(b), and (c) O —Br —OCH₂CH₃ —H I366(a), (b), and (c) O —Br —OCF₃ —HI367(a), (b), and (c) O —Br -tert-butyl —H I368(a), (b), and (c) O —Br-iso-propyl —H I369(a), (b), and (c) O —Br —CH₃ —CH₃ I370(a), (b), and(c) O —Br —H —H I371(a), (b), and (c) O —Br —H —Cl I372(a), (b), and (c)O —Br —H —Br I373(a), (b), and (c) O —Br —H —F I374(a), (b), and (c) O—Br —H —CH₃ I375(a), (b), and (c) O —Br —H —CF₃ I376(a), (b), and (c) O—Br —H —OCH₃ I377(a), (b), and (c) O —Br —H —OCH₂CH₃ I378(a), (b), and(c) O —Br —H —OCF₃ I379(a), (b), and (c) O —Br —H -tert-butyl I380(a),(b), and (c) O —Br —H -iso-propyl I381(a), (b), and (c) O —I —Cl —HI382(a), (b), and (c) O —I —Br —H I383(a), (b), and (c) O —I —F —HI384(a), (b), and (c) O —I —CH₃ —H I385(a), (b), and (c) O —I —CF₃ —HI386(a), (b), and (c) O —I —OCH₃ —H I387(a), (b), and (c) O —I —OCH₂CH₃—H I388(a), (b), and (c) O —I —OCF₃ —H I389(a), (b), and (c) O —I-tert-butyl —H I390(a), (b), and (c) O —I -iso-propyl —H I391(a), (b),and (c) O —I —CH₃ —CH₃ I392(a), (b), and (c) O —I —H —H I393(a), (b),and (c) O —I —H —Cl I394(a), (b), and (c) O —I —H —Br I395(a), (b), and(c) O —I —H —F I396(a), (b), and (c) O —I —H —CH₃ I397(a), (b), and (c)O —I —H —CF₃ I398(a), (b), and (c) O —I —H —OCH₃ I399(a), (b), and (c) O—I —H —OCH₂CH₃ I400(a), (b), and (c) O —I —H —OCF₃ I401(a), (b), and (c)O —I —H -tert-butyl I402(a), (b), and (c) O —I —H -iso-propyl I403(a),(b), and (c) NH —Cl —Cl —H I404(a), (b), and (c) NH —Cl —Br —H I405(a),(b), and (c) NH —Cl —F —H I406(a), (b), and (c) NH —Cl —CH₃ —H I407(a),(b), and (c) NH —Cl —CF₃ —H I408(a), (b), and (c) NH —Cl —OCH₃ —HI409(a), (b), and (c) NH —Cl —OCH₂CH₃ —H I410(a), (b), and (c) NH —Cl—OCF₃ —H I411(a), (b), and (c) NH —Cl -tert-butyl —H I412(a), (b), and(c) NH —Cl -iso-propyl —H I413(a), (b), and (c) NH —Cl —CH₃ —CH₃I414(a), (b), and (c) NH —Cl —H —H I415(a), (b), and (c) NH —Cl —H —CH₃I416(a), (b), and (c) NH —Cl —H —Cl I417(a), (b), and (c) NH —Cl —H —BrI418(a), (b), and (c) NH —Cl —H —F I419(a), (b), and (c) NH —Cl —H —CF₃I420(a), (b), and (c) NH —Cl —H —OCH₃ I421(a), (b), and (c) NH —Cl —H—OCH₂CH₃ I422(a), (b), and (c) NH —Cl —H —OCF₃ I423(a), (b), and (c) NH—Cl —H -tert-butyl I424(a), (b), and (c) NH —Cl —H -iso-propyl I425(a),(b), and (c) NH —Cl —H —OCF₃ I426(a), (b), and (c) NH —Cl —H -tert-butylI427(a), (b), and (c) NH —Cl —H -iso-propyl I428(a), (b), and (c) NH—CH₃ —Cl —H I429(a), (b), and (c) NH —CH₃ —Br —H I430(a), (b), and (c)NH —CH₃ —F —H I431(a), (b), and (c) NH —CH₃ —CH₃ —H I432(a), (b), and(c) NH —CH₃ —CF₃ —H I433(a), (b), and (c) NH —CH₃ —OCH₃ —H I434(a), (b),and (c) NH —CH₃ —OCH₂CH₃ —H I435(a), (b), and (c) NH —CH₃ —OCF₃ —HI436(a), (b), and (c) NH —CH₃ -tert-butyl —H I437(a), (b), and (c) NH—CH₃ -iso-propyl —H I438(a), (b), and (c) NH —CH₃ —CH₃ —CH₃ I439(a),(b), and (c) NH —CH₃ —H —H I440(a), (b), and (c) NH —CH₃ —H —Cl I441(a),(b), and (c) NH —CH₃ —H —Br I442(a), (b), and (c) NH —CH₃ —H —F I443(a),(b), and (c) NH —CH₃ —H —CH₃ I444(a), (b), and (c) NH —CH₃ —H —CF₃I445(a), (b), and (c) NH —CH₃ —H —OCH₃ I446(a), (b), and (c) NH —CH₃ —H—OCH₂CH₃ I447(a), (b), and (c) NH —CH₃ —H —OCF₃ I448(a), (b), and (c) NH—CH₃ —H -tert-butyl I449(a), (b), and (c) NH —CH₃ —H -iso-propylI450(a), (b), and (c) NH —CF₃ —Cl —H I451(a), (b), and (c) NH —CF₃ —Br—H I452(a), (b), and (c) NH —CF₃ —F —H I453(a), (b), and (c) NH —CF₃—CH₃ —H I454(a), (b), and (c) NH —CF₃ —CF₃ —H I455(a), (b), and (c) NH—CF₃ —OCH₃ —H I456(a), (b), and (c) NH —CF₃ —OCH₂CH₃ —H I457(a), (b),and (c) NH —CF₃ —OCF₃ —H I458(a), (b), and (c) NH —CF₃ -tert-butyl —HI459(a), (b), and (c) NH —CF₃ -iso-propyl —H I460(a), (b), and (c) NH—CF₃ —CH₃ —CH₃ I461(a), (b), and (c) NH —CF₃ —H —H I462(a), (b), and (c)NH —CF₃ —H —Cl I463(a), (b), and (c) NH —CF₃ —H —Br I464(a), (b), and(c) NH —CF₃ —H —F I465(a), (b), and (c) NH —CF₃ —H —CH₃ I466(a), (b),and (c) NH —CF₃ —H —CF₃ I467(a), (b), and (c) NH —CF₃ —H —OCH₃ I468(a),(b), and (c) NH —CF₃ —H —OCH₂CH₃ I469(a), (b), and (c) NH —CF₃ —H —OCF₃I470(a), (b), and (c) NH —CF₃ —H -tert-butyl I471(a), (b), and (c) NH—CF₃ —H -iso-propyl I472(a), (b), and (c) NH —CHF₂ —Cl —H I473(a), (b),and (c) NH —CHF₂ —Br —H I474(a), (b), and (c) NH —CHF₂ —F —H I475(a),(b), and (c) NH —CHF₂ —CH₃ —H I476(a), (b), and (c) NH —CHF₂ —CF₃ —HI477(a), (b), and (c) NH —CHF₂ —OCH₃ —H I478(a), (b), and (c) NH —CHF₂—OCH₂CH₃ —H I479(a), (b), and (c) NH —CHF₂ —OCF₃ —H I480(a), (b), and(c) NH —CHF₂ -tert-butyl —H I481(a), (b), and (c) NH —CHF₂ -iso-propyl—H I482(a), (b), and (c) NH —CHF₂ —CH₃ —CH₃ I483(a), (b), and (c) NH—CHF₂ —H —H I484(a), (b), and (c) NH —CHF₂ —H —Cl I485(a), (b), and (c)NH —CHF₂ —H —Br I486(a), (b), and (c) NH —CHF₂ —H —F I487(a), (b), and(c) NH —CHF₂ —H —CH₃ I488(a), (b), and (c) NH —CHF₂ —H —CF₃ I489(a),(b), and (c) NH —CHF₂ —H —OCH₃ I490(a), (b), and (c) NH —CHF₂ —H—OCH₂CH₃ I491(a), (b), and (c) NH —CHF₂ —H —OCF₃ I492(a), (b), and (c)NH —CHF₂ —H -tert-butyl I493(a), (b), and (c) NH —CHF₂ —H -iso-propylI494(a), (b), and (c) NH —OH —Cl —H I495(a), (b), and (c) NH —OH —Br —HI496(a), (b), and (c) NH —OH —F —H I497(a), (b), and (c) NH —OH —CH₃ —HI498(a), (b), and (c) NH —OH —CF₃ —H I499(a), (b), and (c) NH —OH —OCH₃—H I500(a), (b), and (c) NH —OH —OCH₂CH₃ —H I501(a), (b), and (c) NH —OH—OCF₃ —H I502(a), (b), and (c) NH —OH -tert-butyl —H I503(a), (b), and(c) NH —OH -iso-propyl —H I504(a), (b), and (c) NH —OH —CH₃ —CH₃I505(a), (b), and (c) NH —OH —H —H I506(a), (b), and (c) NH —OH —H —ClI507(a), (b), and (c) NH —OH —H —Br I508(a), (b), and (c) NH —OH —H —FI509(a), (b), and (c) NH —OH —H —CH₃ I510(a), (b), and (c) NH —OH —H—CF₃ I511(a), (b), and (c) NH —OH —H —OCH₃ I512(a), (b), and (c) NH —OH—H —OCH₂CH₃ I513(a), (b), and (c) NH —OH —H —OCF₃ I514(a), (b), and (c)NH —OH —H -tert-butyl I515(a), (b), and (c) NH —OH —H -iso-propylI516(a), (b), and (c) NH —NO₂ —Cl —H I517(a), (b), and (c) NH —NO₂ —Br—H I518(a), (b), and (c) NH —NO₂ —F —H I519(a), (b), and (c) NH —NO₂—CH₃ —H I520(a), (b), and (c) NH —NO₂ —CF₃ —H I521(a), (b), and (c) NH—NO₂ —OCH₃ —H I522(a), (b), and (c) NH —NO₂ —OCH₂CH₃ —H I523(a), (b),and (c) NH —NO₂ —OCF₃ —H I524(a), (b), and (c) NH —NO₂ -tert-butyl —HI525(a), (b), and (c) NH —NO₂ -iso-propyl —H I526(a), (b), and (c) NH—NO₂ —CH₃ —CH₃ I527(a), (b), and (c) NH —NO₂ —H —H I528(a), (b), and (c)NH —NO₂ —H —Cl I529(a), (b), and (c) NH —NO₂ —H —Br I530(a), (b), and(c) NH —NO₂ —H —F I531(a), (b), and (c) NH —NO₂ —H —CH₃ I532(a), (b),and (c) NH —NO₂ —H —CF₃ I533(a), (b), and (c) NH —NO₂ —H —OCH₃ I534(a),(b), and (c) NH —NO₂ —H —OCH₂CH₃ I535(a), (b), and (c) NH —NO₂ —H —OCF₃I536(a), (b), and (c) NH —NO₂ —H -tert-butyl I537(a), (b), and (c) NH—NO₂ —H -iso-propyl I538(a), (b), and (c) NH —CN —Br —H I539(a), (b),and (c) NH —CN —Cl —H I540(a), (b), and (c) NH —CN —F —H I541(a), (b),and (c) NH —CN —CH₃ —H I542(a), (b), and (c) NH —CN —CF₃ —H I543(a),(b), and (c) NH —CN —OCH₃ —H I544(a), (b), and (c) NH —CN —OCH₂CH₃ —HI545(a), (b), and (c) NH —CN —OCF₃ —H I546(a), (b), and (c) NH —CN-tert-butyl —H I547(a), (b), and (c) NH —CN -iso-propyl —H I548(a), (b),and (c) NH —CN —CH₃ —CH₃ I549(a), (b), and (c) NH —CN —H —H I550(a),(b), and (c) NH —CN —H —Cl I551(a), (b), and (c) NH —CN —H —Br I552(a),(b), and (c) NH —CN —H —F I553(a), (b), and (c) NH —CN —H —CH₃ I554(a),(b), and (c) NH —CN —H —CF₃ I555(a), (b), and (c) NH —CN —H —OCH₃I556(a), (b), and (c) NH —CN —H —OCH₂CH₃ I557(a), (b), and (c) NH —CN —H—OCF₃ I558(a), (b), and (c) NH —CN —H -tert-butyl I559(a), (b), and (c)NH —CN —H -iso-propyl I560(a), (b), and (c) NH —Br —Br —H I561(a), (b),and (c) NH —Br —Cl —H I562(a), (b), and (c) NH —Br —F —H I563(a), (b),and (c) NH —Br —CH₃ —H I564(a), (b), and (c) NH —Br —CF₃ —H I565(a),(b), and (c) NH —Br —OCH₃ —H I566(a), (b), and (c) NH —Br —OCH₂CH₃ —HI567(a), (b), and (c) NH —Br —OCF₃ —H I568(a), (b), and (c) NH —Br-tert-butyl —H I569(a), (b), and (c) NH —Br -iso-propyl —H I570(a), (b),and (c) NH —Br —CH₃ —CH₃ I571(a), (b), and (c) NH —Br —H —H I572(a),(b), and (c) NH —Br —H —Cl I573(a), (b), and (c) NH —Br —H —Br I574(a),(b), and (c) NH —Br —H —F I575(a), (b), and (c) NH —Br —H —CH₃ I576(a),(b), and (c) NH —Br —H —CF₃ I577(a), (b), and (c) NH —Br —H —OCH₃I578(a), (b), and (c) NH —Br —H —OCH₂CH₃ I579(a), (b), and (c) NH —Br —H—OCF₃ I580(a), (b), and (c) NH —Br —H -tert-butyl I581(a), (b), and (c)NH —Br —H -iso-propyl I582(a), (b), and (c) NH —I —Cl —H I583(a), (b),and (c) NH —I —Br —H I584(a), (b), and (c) NH —I —F —H I585(a), (b), and(c) NH —I —CH₃ —H I586(a), (b), and (c) NH —I —CF₃ —H I587(a), (b), and(c) NH —I —OCH₃ —H I588(a), (b), and (c) NH —I —OCH₂CH₃ —H I589(a), (b),and (c) NH —I —OCF₃ —H I590(a), (b), and (c) NH —I -tert-butyl —HI591(a), (b), and (c) NH —I -iso-propyl —H I592(a), (b), and (c) NH —I—CH₃ —CH₃ I593(a), (b), and (c) NH —I —H —H I594(a), (b), and (c) NH —I—H —Cl I595(a), (b), and (c) NH —I —H —Br I596(a), (b), and (c) NH —I —H—F I597(a), (b), and (c) NH —I —H —CH₃ I598(a), (b), and (c) NH —I —H—CF₃ I599(a), (b), and (c) NH —I —H —OCH₃ I600(a), (b), and (c) NH —I —H—OCH₂CH₃ I601(a), (b), and (c) NH —I —H —OCF₃ I602(a), (b), and (c) NH—I —H -tert-butyl I603(a), (b), and (c) NH —I —H -iso-propyl (a) meansthat R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is—H. (c) means that R₁₂ and R₁₄ are each —H.

TABLE 10 (IIb)

and pharmaceutically acceptable salts thereof, where: Compound R₁ R₈J01(a), (b), and (c) —Cl —H J02(a), (b), and (c) —Cl -t-butyl J03(a),(b), and (c) —Cl -iso-butyl J04(a), (b), and (c) —Cl -sec-butyl J05(a),(b), and (c) —Cl -iso-propyl J06(a), (b), and (c) —Cl -n-propyl J07(a),(b), and (c) —Cl -cyclohexyl J08(a), (b), and (c) —Cl -t-butoxy J09(a),(b), and (c) —Cl -iso-propoxy J10(a), (b), and (c) —Cl —CF₃ J11(a), (b),and (c) —Cl —CH₂CF₃ J12(a), (b), and (c) —Cl —OCF₃ J13(a), (b), and (c)—Cl —Cl J14(a), (b), and (c) —Cl —Br J15(a), (b), and (c) —Cl —I J16(a),(b), and (c) —Cl -n-butyl J17(a), (b), and (c) —Cl -n-propyl J18(a),(b), and (c) —F —H J19(a), (b), and (c) —F -t-butyl J20(a), (b), and (c)—F -iso-butyl J21(a), (b), and (c) —F -sec-butyl J22(a), (b), and (c) —F-iso-propyl J23(a), (b), and (c) —F -n-propyl J24(a), (b), and (c) —F-cyclohexyl J25(a), (b), and (c) —F -t-butoxy J26(a), (b), and (c) —F-iso-propoxy J27(a), (b), and (c) —F —CF₃ J28(a), (b), and (c) —F—CH₂CF₃ J29(a), (b), and (c) —F —OCF₃ J30(a), (b), and (c) —F —ClJ31(a), (b), and (c) —F —Br J32(a), (b), and (c) —F —I J33(a), (b), and(c) —F -n-butyl J34(a), (b), and (c) —F -n-propyl J35(a), (b), and (c)—CH₃ —H J36(a), (b), and (c) —CH₃ -iso-butyl J37(a), (b), and (c) —CH₃-t-butyl J38(a), (b), and (c) —CH₃ -sec-butyl J39(a), (b), and (c) —CH₃-iso-propyl J40(a), (b), and (c) —CH₃ -n-propyl J41(a), (b), and (c)—CH₃ -cyclohexyl J42(a), (b), and (c) —CH₃ -t-butoxy J43(a), (b), and(c) —CH₃ -iso-propoxy J44(a), (b), and (c) —CH₃ —CF₃ J45(a), (b), and(c) —CH₃ —CH₂CF₃ J46(a), (b), and (c) —CH₃ —OCF₃ J47(a), (b), and (c)—CH₃ —Cl J48(a), (b), and (c) —CH₃ —Br J49(a), (b), and (c) —CH₃ —IJ50(a), (b), and (c) —CH₃ -n-butyl J51(a), (b), and (c) —CH₃ -n-propylJ52(a), (b), and (c) —CF₃ —H J53(a), (b), and (c) —CF₃ -t-butyl J54(a),(b), and (c) —CF₃ -iso-butyl J55(a), (b), and (c) —CF₃ -sec-butylJ56(a), (b), and (c) —CF₃ -iso-propyl J57(a), (b), and (c) —CF₃-n-propyl J58(a), (b), and (c) —CF₃ -cyclohexyl J59(a), (b), and (c)—CF₃ -t-butoxy J60(a), (b), and (c) —CF₃ -iso-propoxy J61(a), (b), and(c) —CF₃ —CF₃ J62(a), (b), and (c) —CF₃ —CH₂CF₃ J63(a), (b), and (c)—CF₃ —OCF₃ J64(a), (b), and (c) —CF₃ —Cl J65(a), (b), and (c) —CF₃ —BrJ66(a), (b), and (c) —CF₃ —I J67(a), (b), and (c) —CF₃ -n-butyl J68(a),(b), and (c) —CF₃ -n-propyl J69(a), (b), and (c) —CHF₂ -t-butyl J70(a),(b), and (c) —CHF₂ —H J71(a), (b), and (c) —CHF₂ -iso-butyl J72(a), (b),and (c) —CHF₂ -sec-butyl J73(a), (b), and (c) —CHF₂ -iso-propyl J74(a),(b), and (c) —CHF₂ -n-propyl J75(a), (b), and (c) —CHF₂ -cyclohexylJ76(a), (b), and (c) —CHF₂ -t-butoxy J77(a), (b), and (c) —CHF₂-iso-propoxy J78(a), (b), and (c) —CHF₂ —CF₃ J79(a), (b), and (c) —CHF₂—CH₂CF₃ J80(a), (b), and (c) —CHF₂ —OCF₃ J81(a), (b), and (c) —CHF₂ —ClJ82(a), (b), and (c) —CHF₂ —Br J83(a), (b), and (c) —CHF₂ —I J84(a),(b), and (c) —CHF₂ -n-butyl J85(a), (b), and (c) —CHF₂ -n-propyl J86(a),(b), and (c) —OH —H J87(a), (b), and (c) —OH -t-butyl J88(a), (b), and(c) —OH -iso-butyl J89(a), (b), and (c) —OH -sec-butyl J90(a), (b), and(c) —OH -iso-propyl J91(a), (b), and (c) —OH -n-propyl J92(a), (b), and(c) —OH -cyclohexyl J93(a), (b), and (c) —OH -t-butoxy 794(a), (b), and(c) —OH -iso-propoxy J95(a), (b), and (c) —OH —CF₃ J96(a), (b), and (c)—OH —CH₂CF₃ J97(a), (b), and (c) —OH —OCF₃ J98(a), (b), and (c) —OH —ClJ99(a), (b), and (c) —OH —Br J100(a), (b), and (c) —OH —I J101(a), (b),and (c) —OH -n-butyl J102(a), (b), and (c) —OH -n-propyl J103(a), (b),and (c) —NO₂ —H J104(a), (b), and (c) —NO₂ -t-butyl J105(a), (b), and(c) —NO₂ -iso-butyl J106(a), (b), and (c) —NO₂ -sec-butyl J107(a), (b),and (c) —NO₂ -iso-propyl J108(a), (b), and (c) —NO₂ -n-propyl J109(a),(b), and (c) —NO₂ -cyclohexyl J110(a), (b), and (c) —NO₂ -t-butoxyJ111(a), (b), and (c) —NO₂ -iso-propoxy J112(a), (b), and (c) —NO₂ —CF₃J113(a), (b), and (c) —NO₂ —CH₂CF₃ J114(a), (b), and (c) —NO₂ —OCF₃J115(a), (b), and (c) —NO₂ —Cl J116(a), (b), and (c) —NO₂ —Br J117(a),(b), and (c) —NO₂ —I J118(a), (b), and (c) —NO₂ -n-butyl J119(a), (b),and (c) —NO₂ -n-propyl J120(a), (b), and (c) —CN —H J121(a), (b), and(c) —CN -t-butyl J122(a), (b), and (c) —CN -iso-butyl J123(a), (b), and(c) —CN -sec-butyl J124(a), (b), and (c) —CN -iso-propyl J125(a), (b),and (c) —CN -n-propyl J126(a), (b), and (c) —CN -cyclohexyl J127(a),(b), and (c) —CN -t-butoxy J128(a), (b), and (c) —CN -iso-propoxyJ129(a), (b), and (c) —CN —CF₃ J130(a), (b), and (c) —CN —CH₂CF₃J131(a), (b), and (c) —CN —OCF₃ J132(a), (b), and (c) —CN —Cl J133(a),(b), and (c) —CN —Br J134(a), (b), and (c) —CN —I J135(a), (b), and (c)—CN -n-butyl J136(a), (b), and (c) —CN -n-propyl J137(a), (b), and (c)—Br —H J138(a), (b), and (c) —Br -t-butyl J139(a), (b), and (c) —Br-iso-butyl J140(a), (b), and (c) —Br -sec-butyl J141(a), (b), and (c)—Br -iso-propyl J142(a), (b), and (c) —Br -n-propyl J143(a), (b), and(c) —Br -cyclohexyl J144(a), (b), and (c) —Br -t-butoxy J145(a), (b),and (c) —Br -iso-propoxy J146(a), (b), and (c) —Br —CF₃ J147(a), (b),and (c) —Br —CH₂CF₃ J148(a), (b), and (c) —Br —OCF₃ J149(a), (b), and(c) —Br —Cl J150(a), (b), and (c) —Br —Br J151(a), (b), and (c) —Br —IJ152(a), (b), and (c) —Br -n-butyl J153(a), (b), and (c) —Br -n-propylJ154(a), (b), and (c) —I -t-butyl J155(a), (b), and (c) —I —H J156(a),(b), and (c) —I -iso-butyl J157(a), (b), and (c) —I -sec-butyl J158(a),(b), and (c) —I -iso-propyl J159(a), (b), and (c) —I -n-propyl J160(a),(b), and (c) —I -cyclohexyl J161(a), (b), and (c) —I -t-butoxy J162(a),(b), and (c) —I -iso-propoxy J163(a), (b), and (c) —I —CF₃ J164(a), (b),and (c) —I —CH₂CF₃ J165(a), (b), and (c) —I —OCF₃ J166(a), (b), and (c)—I —Cl J167(a), (b), and (c) —I —Br J168(a), (b), and (c) —I —I J169(a),(b), and (c) —I -n-butyl J170(a), (b), and (c) —I -n-propyl (a) meansthat R₁₂ is —H and R₁₄ is —CH₃. (b) means that R₁₂ is —CH₃ and R₁₄ is—H. (c) means that R₁₂ and R₁₄ are each —H.

4.3 Definitions

As used in connection with the Cycloheteroalkenyl Compounds herein, theterms used above having following meaning:

“—(C₁-C₁₀)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 10 carbon atoms. Representative straightchain —(C₁-C₁₀)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, -n-hexyl, -n-heptyl, -n-octyl, -n-nonyl, and -n-decyl.Representative branched —(C₁-C₁₀)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, -tert-butyl, -iso-pentyl, -neo-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1-ethylbutyl, 2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl,2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-methylhexyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,2-dimethylpentyl,1,3-dimethylpentyl, 1,2-dimethylhexyl, 1,3-dimethylhexyl,3,3-dimethylhexyl, 1,2-dimethylheptyl, 1,3-dimethylheptyl, and3,3-dimethylheptyl.

“—(C₁-C₆)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 6 carbon atoms. Representative straightchain —(C₁-C₆)alkyls include -methyl, -ethyl, -n-propyl, -n-butyl,-n-pentyl, and -n-hexyl. Representative branched —(C₁-C₆)alkyls include-iso-propyl, -sec-butyl, -iso-butyl, -tert-butyl, -iso-pentyl,-neo-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl,3-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having from 1 to 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“—(C₂-C₁₀)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₁₀)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, -2-hexenyl,-3-hexenyl, -1-heptenyl, -2-heptenyl, -3-heptenyl, -1-octenyl,-2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl, -3-nonenyl, -1-decenyl,-2-decenyl, -3-decenyl and the like.

“—(C₂-C₆)alkenyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon double bond. Representative straight chain and branched(C₂-C₆)alkenyls include -vinyl, -allyl, -1-butenyl, -2-butenyl,-iso-butylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl,-2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, -1-hexenyl, 2-hexenyl,3-hexenyl and the like.

“—(C₂-C₁₀)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 10 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched—(C₂-C₁₀)alkynyls include -acetylenyl, -propynyl, -1-butynyl,-2-butynyl, -1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl,-1-hexynyl, -2-hexynyl, -5-hexynyl, -1-heptynyl, -2-heptynyl,-6-heptynyl, -1-octynyl, -2-octynyl, -7-octynyl, -1-nonynyl, -2-nonynyl,-8-nonynyl, -1-decynyl, -2-decynyl, -9-decynyl and the like.

“—(C₂-C₆)alkynyl” means a straight chain or branched non-cyclichydrocarbon having from 2 to 6 carbon atoms and including at least onecarbon-carbon triple bond. Representative straight chain and branched(C₂-C₆)alkynyls include -acetylenyl, -propynyl, -1-butynyl, -2-butynyl,-1-pentynyl, -2-pentynyl, -3-methyl-1-butynyl, -4-pentynyl, -1-hexynyl,-2-hexynyl, -5-hexynyl and the like.

“—(C₃-C₁₀)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 10 carbon atoms. Representative (C₃-C₁₀)cycloalkyls are -cyclopropyl,-cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl,-cyclononyl, and -cyclodecyl.

“—(C₃-C₈)cycloalkyl” means a saturated cyclic hydrocarbon having from 3to 8 carbon atoms. Representative (C₃-C₈)cycloalkyls include-cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, and-cyclooctyl.

“—(C₈-C₁₄)bicycloalkyl” means a bi-cyclic hydrocarbon ring system havingfrom 8 to 14 carbon atoms and at least one saturated cyclic alkyl ring.Representative —(C₈-C₁₄)bicycloalkyls include -indanyl,-1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl,-perhydronaphthyl and the like.

“—(C₈-C₁₄)tricycloalkyl” means a tri-cyclic hydrocarbon ring systemhaving from 8 to 14 carbon atoms and at least one saturated ring.Representative —(C₈-C₁₄)tricycloalkyls include -pyrenyl,-1,2,3,4-tetrahydroanthracenyl, -perhydroanthracenyl -aceanthreneyl,-1,2,3,4-tetrahydropenanthrenyl, -5,6,7,8-tetrahydrophenanthrenyl,-perhydrophenanthrenyl and the like.

“—(C₅-C₁₀)cycloalkenyl” means a cyclic non-aromatic hydrocarbon havingat least one carbon-carbon double bond in the cyclic system and from 5to 10 carbon atoms. Representative (C₅-C₁₀)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl, -cyclononenyl,-cyclononadienyl, -cyclodecenyl, -cyclodecadienyl and the like.

“—(C₅-C₈)cycloalkenyl” means a cyclic non-aromatic hydrocarbon having atleast one carbon-carbon double bond in the cyclic system and from 5 to 8carbon atoms. Representative —(C₅-C₈)cycloalkenyls include-cyclopentenyl, -cyclopentadienyl, -cyclohexenyl, -cyclohexadienyl,-cycloheptenyl, -cycloheptadienyl, -cycloheptatrienyl, -cyclooctenyl,-cyclooctadienyl, -cyclooctatrienyl, -cyclooctatetraenyl and the like.

“—(C₈-C₁₄)bicycloalkenyl” means a bi-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)bicycloalkenyls include-indenyl, -pentalenyl, -naphthalenyl, -azulenyl, -heptalenyl,-1,2,7,8-tetrahydronaphthalenyl and the like.

“—(C₈-C₁₄)tricycloalkenyl” means a tri-cyclic hydrocarbon ring systemhaving at least one carbon-carbon double bond in each ring and from 8 to14 carbon atoms. Representative —(C₈-C₁₄)tricycloalkenyls include-anthracenyl, -phenanthrenyl, -phenalenyl, -acenaphthalenyl,as-indacenyl, s-indacenyl and the like.

“—(3- to 7-membered)heterocycle” or “-(3- to 7-membered)heterocyclo”means a 3- to 7-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, a 5-membered heterocyclecan contain up to 4 heteroatoms, a 6-membered heterocycle can contain upto 6 heteroatoms, and a 7-membered heterocycle can contain up to 7heteroatoms. Each heteroatom is independently selected from nitrogen,which can be quaternized; oxygen; and sulfur, including sulfoxide andsulfone. The -(3- to 7-membered)heterocycle can be attached via anitrogen or carbon atom. Representative -(3- to 7-membered)heterocyclesinclude pyridyl, furyl, thiophenyl, pyrrolyl, oxazolyl, imidazolyl,thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyrimidinyl, triazinyl, morpholinyl,pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl,valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl,tetrahydrothiophenyl, tetrahydrothiopyranyl and the like.

“-(3- to 5-membered)heterocycle” or “-(3- to 5-membered)heterocyclo”means a 3- to 5-membered monocyclic heterocyclic ring which is eithersaturated, unsaturated non-aromatic, or aromatic. A 3- or a 4-memberedheterocycle can contain up to 3 heteroatoms, and a 5-memberedheterocycle can contain up to 4 heteroatoms. Each heteroatom isindependently selected from nitrogen, which can be quaternized; oxygen;and sulfur, including sulfoxide and sulfone. The -(3- to5-membered)heterocycle can be attached via a nitrogen or carbon atom.Representative -(3- to 5-membered)heterocycles include furyl,thiophenyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,pyrazolyl, isothiazolyl, triazinyl, pyrrolidinonyl, pyrrolidinyl,hydantoinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyland the like.

“-(7- to 10-membered)bicycloheterocycle” or “-(7- to10-membered)bicycloheterocyclo” means a 7- to 10-membered bicyclic,heterocyclic ring which is either saturated, unsaturated non-aromatic,or aromatic. A -(7- to 10-membered)bicycloheterocycle contains from 1 to4 heteroatoms independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(7- to 10-membered)bicycloheterocycle can be attached via a nitrogen orcarbon atom. Representative -(7- to 10-membered)bicycloheterocyclesinclude -quinolinyl, -isoquinolinyl, -chromonyl, -coumarinyl, -indolyl,-indolizinyl, -benzo[b]furanyl, -benzo[b]thiophenyl, -indazolyl,-purinyl, -4H-quinolizinyl, -isoquinolyl, -quinolyl, -phthalazinyl,-naphthyridinyl, -carbazolyl, -β-carbolinyl and the like.

“—(C₁₄)aryl” means a 14-membered aromatic carbocyclic moiety such as-anthryl or -phenanthryl.

“-(5- to 10-membered)heteroaryl” means an aromatic heterocycle ring of 5to 10 members, including both mono- and bicyclic ring systems, where atleast one carbon atom of one or both of the rings is replaced with aheteroatom independently selected from nitrogen, oxygen, and sulfur. Inone embodiment, one of the -(5- to 10-membered)heteroaryl's ringscontain at least one carbon atom. In another embodiment, both of the-(5- to 10-membered)heteroaryl's rings contain at least one carbon atom.Representative -(5- to 10-membered)heteroaryls include pyridyl, furyl,benzofuranyl, thiophenyl, benzothiophenyl, quinolinyl, pyrrolyl,indolyl, oxazolyl, benzoxazolyl, imidazolyl, benzimidazolyl, thiazolyl,benzothiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, pyridazinyl,pyrimidinyl, pyrimidinyl, thiadiazolyl, triazinyl, cinnolinyl,phthalazinyl, and quinazolinyl.

“—CH₂(halo)” means a methyl group where one of the hydrogens of themethyl group has been replaced with a halogen. Representative —CH₂(halo)groups include —CH₂F, —CH₂Cl, —CH₂Br, and —CH₂I.

“—CH(halo)₂” means a methyl group where two of the hydrogens of themethyl group have been replaced with a halogen. Representative—CH(halo)₂ groups include —CHF₂, —CHCl₂, —CHBr₂, —CHBrCl, —CHClI, and—CHI₂.

“—C(halo)₃” means a methyl group where each of the hydrogens of themethyl group has been replaced with a halogen. Representative —C(halo)₃groups include —CF₃, —CCl₃, —CBr₃, and —CI₃.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

The phrase “pyridyl group” means

where R₁, R₂, and n are defined above for the CycloheteroalkenylCompounds of formula (II).

The phrase “pyrazinyl group” means,

where R₁, R₂, and p are defined above for the CycloheteroalkenylCompounds of formula (I).

The phrase “pyrimidinyl group” means

where R₁, R₂, and p are defined above for the CycloheteroalkenylCompounds of formula (I).

The phrase “pyridazinyl group” means

where R₁, R₂, and p are defined above for the CycloheteroalkenylCompounds of formula (I).

The phrase “thiadiazolyl group” means

where R₁ is defined above for the Cycloheteroalkenyl Compounds offormula (I).

The phrase “benzoimidiazolyl group” means

where R₈ and s is defined above for the Cycloheteroalkenyl Compounds offormula (I) or (II).

The phrase “benzothiazolyl group” means

where R₈ and s is defined above for the Cycloheteroalkenyl Compounds offormula (I) or (II).

The phrase “benzooxazolyl group” means

where R₈ and s is defined above for the Cycloheteroalkenyl Compounds offormula (I) or (II).

The phrase “Cycloheteroalkenyl ring” means

where the numbers designate the position of each atom of theCycloheteroalkenyl ring.

The term “animal,” includes, but is not limited to, a cow, monkey,baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, guinea pig, and human.

The phrase “pharmaceutically acceptable salt,” as used herein, is anypharmaceutically acceptable salt that can be prepared from aCycloheteroalkenyl Compound, including a salt formed from an acid and abasic functional group, such as a nitrogen group, of one of theCycloheteroalkenyl Compounds. Illustrative salts include, but are notlimited, to sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucoronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term“pharmaceutically acceptable salt” also includes a salt prepared from aCycloheteroalkenyl Compound having an acidic functional group, such as acarboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine and the like.

The phrase “effective amount,” when used in connection with aCycloheteroalkenyl Compound means an amount effective for: (a) treatingor preventing a Condition; or (b) inhibiting VR1, mGluR1, or mGluR5function in a cell.

The phrase “effective amount,” when used in connection with the anothertherapeutic agent means an amount for providing the therapeutic effectof the therapeutic agent.

When a first group is “substituted with one or more” second groups, oneor more hydrogen atoms of the first group is replaced with acorresponding number of second groups. When the number of second groupsis two or greater, each second group can be the same or different. Inone embodiment, the number of second groups is one or two. In anotherembodiment, the number of second groups is one.

The term “THF” means tetrahydrofuran.

The term “DCM” means dichloromethane.

The term “DMF” means dimethylformamide.

The term “DAST” means diethylaminosulfur trifluoride.

The term “DMSO” means dimethyl sulfoxide.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The term “LiHMDS” means lithium hexamethyldisilazide.

The phrases “treatment of,” “treating” and the like include theamelioration or cessation of a Condition or a symptom thereof.

In one embodiment, treating includes inhibiting, for example, decreasingthe overall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of,” “preventing” and the like include theavoidance of the onset of a Condition or a symptom thereof

4.4 Methods for Making the Cycloheteroalkenyl Compounds

The Cycloheteroalkenyl Compounds can be made using conventional organicsynthesis or by the following illustrative methods shown in the schemesbelow.

4.4.1 Methods for Making the Cycloheteroalkenyl Compounds Where X is O

The Cycloheteroalkenyl Compounds where X is O can be obtained by thefollowing illustrative method shown below in Schemes 1 and 2.

where R₃, Ar₂, and m, are defined above.

To a solution of ketal 1 (about 14 mmol) in DCM (about 7 mL) is added anisocyanate of formula Ar₂—NCO (about 14 mmol) 2 and the resultingsolution is allowed to stir at about 25° C. Typically, the reactionmixture is allowed to stir for at least 5 min. The solvent is thenremoved to provide a compound of formula 3, which is dissolved in THF(about 20 mL). About 1 N HCl in acetic acid (about 30 mL) is added tothe THF solution of the compound of formula 3, and the resulting mixtureis heated at the reflux temperature of the solvent. Typically, thereaction mixture is heated at the reflux temperature of the solvent forabout 3 h. The reaction mixture is then cooled and the solvent isremoved to provide a residue that is dissolved in DCM. The DCM solutionis then extracted with aq. Na₂CO₃, the aqueous and organic layers areseparated, and the organic layer is extracted three times with DCM. Theorganic layers are combined, dried with MgSO₄, and the solvent isremoved to provide a compound of formula 4. The compound of formula 4can be purified. In one embodiment, the compound of formula 4 ispurified using silica gel column chromatography.

The compound of formula 4 (about 3.6 mmol) is then dissolved in THF(about 100 mL) and the resulting solution cooled to about −78° C. To thecooled solution is added LiHMDS (about 8.75 mmol) and the reactionmixture is stirred at about −78° C. for about 2 h. A compound of formula5 (about 3.6 mmol, commercially available from Sigma-Aldrich, St. Louis,Mo. (www.sigma-aldrich.com)) is then added to the reaction mixture andthe reaction mixture is stirred at about −78° C. for about 2 h. Thereaction mixture is then allowed to warm to about 25° C. and the solventis removed to provide a compound of formula 6. The compound of formula 6can be purified.

The compound of formula 6 is then reacted with a compound of formula7a-e to provide the Cycloheteroalkenyl Compound where X is O as shownbelow in Scheme 2.

where R₁, R₂, R₃, Ar₁, n, m, and p are defined above.

Pd(PPh)₃ (0.11 mmol) is dissolved in THF (about 50 mL) and the compoundof formula 6 (about 2.2 mmol) is added to the resulting solutionfollowed by a compound of formula 7a-e (about 6.6 mmol as a 0.5 Msolution in THF). The resulting reaction mixture is then heated forabout 1 h at the reflux temperature of the solvent. The reaction mixtureis allowed to cool to about 25° C. and the solvent is removed to providethe Cycloheteroalkenyl Compound where X is O. The CycloheteroalkenylCompound where X is O can be purified. In one embodiment, theCycloheteroalkenyl Compound where X is O is purified using silica gelcolumn chromatography followed by trituration with ethyl acetate.

Where m=1, a mixture of Cycloheteroalkenyl compounds is generallyobtained. The mixture can be separated via conventional methods, forexample, column chromatography.

The compounds of formula 1 are commercially available or can be obtainedby methods known to those skilled in the art.

Isocyanates of formula Ar₂—NCO, 2, are commercially available or arepreparable by reacting an amine Ar₂NH₂ with phosgene according to knownmethods (See, e.g., H. Eckert and B. Foster, Angew. Chem. Int. Ed.Engl., 26:894 (1987); H. Eckert, Ger. Offen. DE 3 440 141; Chem. Abstr.106:4294d (1987); and L. Contarca et al., Synthesis, 553-576 (1996). Forexample, an amine Ar₂NH₂ can be reacted with triphosgene according tothe scheme shown below.

Typically a solution of triphosgene (about 0.3 eq.) in DCM (about 0.3M)is slowly added to a stirred solution of the amine (about 1.0 eq.) inDCM (about 0.3M) at about 25° C. The reaction mixture is then stirred atabout 25° C. for about 10 min. and the temperature then raised to about70° C. After stirring at about 70° C. for about 3 h, the reactionmixture is cooled to about 25° C., filtered, and the filtrateconcentrated to give the desired isocyanate.

The compounds of formula 7a-e can be obtained by methods known to thoseskilled in the art.

4.4.2 Methods for Making the Cycloheteroalkenyl Compounds Where X is S

The Cycloheteroalkenyl Compounds where X is S can be obtained by methodsanalagous to that described in Schemes 1 and 2 to provide theCycloheteroalkenyl Compounds where X is O, except that an isothiocyanateof formula Ar₂—NCS is used in place of the isocyanate Ar₂—NCO.

Where m=1, a mixture of Cycloheteroalkenyl compounds is generallyobtained. The mixture can be separated via conventional methods, forexample, column chromatography.

Isothiocyanates are commercially available or preparable by reacting anamine of formula Ar₂NH₂ with thiophosgene as shown in the scheme below(See, e.g., Tetrahedron Lett., 41(37):7207-7209 (2000); Org. Prep.Proced., Int., 23(6):729-734 (1991); J. Heterocycle Chem., 28(4):1091-1097 (1991); J. Fluorine Chem., 41(3):303-310 (1988); andTetrahedron. Lett., 42(32):5414-5416 (2001).

Alternatively, isothiocyanates of formula Ar₂—NCS can be prepared byreacting an amine of formula Ar₂NH₂ with carbon disulfide in thepresence of triethylamine in THF, followed by reaction with hydrogenperoxide and hydrochloric acid in water as shown in the scheme below(See, e.g., J. Org. Chem., 62(13):4539-4540 (1997)).

4.4.3 Methods for Making the Cycloheteroalkenyl Compounds Where X isN—CN

The Cycloheteroalkenyl Compounds where X is N—CN can be obtained asshown below in Schemes 3 and 4.

where Ar₂, R₃, and m are defined above for the CycloheteroalkenylCompounds.

A ketal of formula 8 (about 14 mmol) is reacted with an amine of formulaAr—NH₂ (about 14 mmol) in an aprotic organic solvent (about 7 mL) suchas diethyl ether, di-n-propyl ether, THF, DCM, or toluene at atemperature ranging from about 25° C. to about the reflux temperature ofthe solvent for a period of about 0.5 h to about 24 h. The solvent isthen removed to provide a compound of formula 9. In one embodiment, theaprotic organic solvent is di-n-propyl ether. In another embodiment, areaction mixture of di-n-propyl ether, a compound of formula 8 and theamine of formula Ar—NH₂ is heated at a temperature of about 70° to about80° C. In another embodiment, the reaction mixture of di-n-propyl ether,a compound of formula 8 and the amine of formula Ar—NH₂ is heated at atemperature of about at 75° C. for about 12 h.

The compound of formula 9 is then dissolved in THF (about 20 mL). About1 N HCl in acetic acid (about 30 mL) is added to the THF solution of thecompound of formula 9 and the resulting mixture is heated at the refluxtemperature of the solvent. Typically, the reaction mixture is heated atthe reflux temperature of the solvent for about 3 h. The reactionmixture is then cooled and the solvent is removed to provide a residuethat is dissolved in DCM. The DCM solution is then extracted with aq.Na₂CO₃, the aqueous and organic layer is separated, and the aqueouslayer is extracted three times with DCM. The combined organic layers arethen dried with MgSO₄ and the solvent removed to provide a compound offormula 10. The compound of formula 10 can be purified. In oneembodiment, the compound of formula 10 is purified using silica gelcolumn chromatography.

The compound of formula 10 (about 3.6 mmol) is then dissolved in THF(about 100 mL) and the resulting solution cooled to about −78° C. To thecooled solution is added LiHMDS (about 8.75 mmol) and the reactionmixture is stirred at about −78° C. for about 2 h. A compound of formula5 (about 3.6 mmol, commercially available from Sigma-Aldrich, St. Louis,Mo. (www.sigma-aldrich.com)) is then added to the reaction mixture andthe reaction mixture stirred at about −78° C. for about 2 h. Thereaction mixture is then allowed to wane to about 25° C. and the solventis removed to provide a compound of formula 11. The compound of formula11 can be purified.

The compound of formula 11 is then reacted with a compound of formula7a-e as shown below in Scheme 4 to provide the CycloheteroalkenylCompound where X is N—CN.

where Ar₂, R₁, R₂, R₃, n, m, and p are defined above for theCycloheteroalkenyl Compounds.

Pd(PPh)₃ is dissolved in THF (about 50 mL) and the compound of formula11 (about 2.2 mmol) is added to the resulting mixture followed by acompound of formula 7a-e (about 6.6 mmol as a 0.5 M solution in THF. Theresulting reaction mixture is then heated for about 1 h at the refluxtemperature of the solvent. The reaction mixture is allowed to cool toabout 25° C. and the solvent removed to provide the CycloheteroalkenylCompound where X is N—CN. The Cycloheteroalkenyl Compound where X isN—CN can be purified. In one embodiment, the Cycloheteroalkenyl Compoundwhere X is N—CN is purified by silica gel column chromatography.

Where m=1, a mixture of Cycloheteroalkenyl compounds is generallyobtained. The mixture can be separated via conventional methods, forexample, column chromatography.

The compound of formula 8 can be obtained as shown below in Scheme 5.

where R₃, and m are defined above for the Cycloheteroalkenyl Compounds.

A compound of formula 1 is reacted with diphenylcyanocarbonimidate 12(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) in an aprotic solvent such as diethyl ether,di-n-propyl ether, THF, DCM, or toluene to provide the compound offormula 8. In one embodiment, the aprotic solvent is DCM and thereaction mixture of the compound of formula 1 anddiphenylcyanocabonimidate 12 is allowed to react at about 25° C. Inanother embodiment, the aprotic solvent is toluene and the reactionmixture of the compound of formula 1 and diphenylcyanocabonimidate 12 isallowed to react at about 110° C. The compound of formula 1 anddiphenylcyanocabonimidate 12 is typically allowed to react for a periodof about 0.5 h to about 24 h.

The compounds of formula 7a-e can be obtained as described above.

4.4.4 Methods for Making the Cycloheteroalkenyl Compounds where X isN—OH

The Cycloheteroalkenyl Compounds where X is N—OH can be obtained asdescribed below in Scheme 6.

where Ar₂, R₁, R₂, R₃, n, m, and p are defined above for theCycloheteroalkenyl Compounds and P is a hydroxyl protecting group.

The method for obtaining the Cycloheteroalkenyl Compounds where X isN—OH as described in Scheme 6 is analogous to that described in Schemes3 and 4 to provide the Cycloheteroalkenyl Compounds where X is N—CNexcept that a compound of formula 13 is used in place of the compound offormula 9.

The compound of formula 13 can be obtained as described below in Scheme7.

where Ar₂, R₃, and m are defined above for the CycloheteroalkenylCompounds and P is a hydroxyl protecting group.

A compound of formula 17 (about 0.3 mmol) is reacted with hydroxylamine(50 weight percent in water, about 5.8 mmol) in about 1.5 mL of ethanolwith stirring at a temperature of about 80° C. for about 2 h. Themixture is then concentrated under reduced pressure to provide acompound of formula 18. The hydroxyl group of the compound of formula 18is then protected using an hydroxyl protecting group to provide thecompound of formula 13. Any hydroxyl protecting group known to thoseskilled in the art can be used to protect the hydroxyl group in thecompound of formula 18. Suitable hydroxyl protecting groups and methodsfor their removal are disclosed in T. W. Greene et al, Protective Groupsin Organic Synthesis 17-200 (3d ed. 1999).

Where m=1, a mixture of Cycloheteroalkenyl compounds is generallyobtained. The mixture can be separated via conventional methods, forexample, column chromatography.

The compound of formula 17 can be obtained as shown below in Scheme 8.

where Ar₂, R₃, and m are defined above for the CycloheteroalkenylCompounds.

A solution of a compound of formula 19 (about 0.6 mmol), obtained asdescribed above in section 4.4.2, in DCM is reacted with iodomethane(about 0.9 mmol) in about 3 mL of tetrahydrofuran with stirring at about25° C. for about 12 h. Excess iodomethane is removed from the mixtureusing reduced pressure. A solution of triethylamine (about 1.74 mmol) inabout 2.5 mL of ethyl acetate is then added to the mixture and themixture is allowed to stir for about 2 h. The mixture is thenconcentrated under reduced pressure to provide the compound of formula17 which can then be purified. In one embodiment, the compound offormula 17 is purified using column chromatography or recrystallization.

4.4.5 Methods for Making the Cycloheteroalkenyl Compounds where X isN—OR₁₀

The Cycloheteroalkenyl Compounds where X is N—OR₁₀ can be obtained byreacting a Cycloheteroalkenyl Compounds where X is N—OH, obtained asdescribed above in Scheme 6, with X—(C₁-C₄)alkyl, where X is —I, —Br,—Cl, or —F, in the presence of about 3 eq. of triethylamine in THF, withstirring, at about 25° C. for about 12 h or at about 50° C. for about 3h. The solvent is then removed from the reaction mixture under reducedpressure to provide a residue. The residue is then purified using silicagel column chromatography eluted with a gradient elution of 100:0hexane:ethyl acetate to 25:75 hexane:ethyl acetate to provide theCycloheteroalkenyl Compounds where X is N—OR₁₀. In one embodiment, X is—I or —Br.

Where m=1, a mixture of Cycloheteroalkenyl Compounds is generallyobtained. The mixture can be separated via conventional methods, forexample, column chromatography.

Certain Cycloheteroalkenyl Compounds can have asymmetric centers andtherefore exist in different enantiomeric and diastereomeric forms. ACycloheteroalkenyl Compound can be in the form of an optical isomer or adiastereomer. Accordingly, the invention encompasses CycloheteroalkenylCompounds and their uses as described herein in the form of theiroptical isomers, diasteriomers and mixtures thereof, including a racemicmixture. Optical isomers of the Cycloheteroalkenyl Compounds can beobtained by known techniques such as chiral chromatography or formationof diastereomeric salts from an optically active acid or base.

In addition, one or more hydrogen, carbon or other atoms of aCycloheteroalkenyl Compound can be replaced by an isotope of thehydrogen, carbon or other atoms. Such compounds, which are encompassedby the present invention, are useful as research and diagnostic tools inmetabolism pharmacokinetic studies and in binding assays.

4.5. Therapeutic Uses of the Cycloheteroalkenyl Compounds

In accordance with the invention, the Cycloheteroalkenyl Compounds areadministered to an animal in need of treatment or prevention of aCondition.

In one embodiment, an effective amount of a Cycloheteroalkenyl Compoundcan be used to treat or prevent any condition treatable or preventableby inhibiting VR1. Examples of conditions that are treatable orpreventable by inhibiting VR1 include, but are not limited to, pain, UI,an ulcer, IBD, and IBS.

In another embodiment, an effective amount of a CycloheteroalkenylCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting mGluR5. Examples of conditions that aretreatable or preventable by inhibiting mGluR5 include, but are notlimited to, pain, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, a pruritic condition, and psychosis.

In another embodiment, an effective amount of a CycloheteroalkenylCompound can be used to treat or prevent any condition treatable orpreventable by inhibiting mGluR1. Examples of conditions that aretreatable or preventable by inhibiting mGluR1 include, but are notlimited to, pain, UI, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, and depression.

The Cycloheteroalkenyl Compounds can be used to treat or prevent acuteor chronic pain. Examples of pain treatable or preventable using theCycloheteroalkenyl Compounds include, but are not limited to, cancerpain, labor pain, myocardial infarction pain, pancreatic pain, colicpain, post-operative pain, headache pain, muscle pain, arthritic pain,and pain associated with a periodontal disease, including gingivitis andperiodontitis.

The Cycloheteroalkenyl Compounds can also be used for treating orpreventing pain associated with inflammation or with an inflammatorydisease in an animal. Such pain can arise where there is an inflammationof the body tissue which can be a local inflammatory response and/or asystemic inflammation. For example, the Cycloheteroalkenyl Compounds canbe used to treat or prevent pain associated with inflammatory diseasesincluding, but not limited to: organ transplant rejection; reoxygenationinjury resulting from organ transplantation (see Grupp et al., J. Mol,Cell Cardiol. 31:297-303 (1999)) including, but not limited to,transplantation of the heart, lung, liver, or kidney; chronicinflammatory diseases of the joints, including arthritis, rheumatoidarthritis, osteoarthritis and bone diseases associated with increasedbone resorption; inflammatory bowel diseases, such as ileitis,ulcerative colitis, Barrett's syndrome, and Crohn's disease;inflammatory lung diseases, such as asthma, adult respiratory distresssyndrome, and chronic obstructive airway disease; inflammatory diseasesof the eye, including corneal dystrophy, trachoma, onchocerciasis,uveitis, sympathetic ophthalmitis and endophthalmitis; chronicinflammatory disease of the gum, including gingivitis and periodontitis;tuberculosis; leprosy; inflammatory diseases of the kidney, includinguremic complications, glomerulonephritis and nephrosis; inflammatorydisease of the skin, including sclerodermatitis, psoriasis and eczema;inflammatory diseases of the central nervous system, including chronicdemyelinating diseases of the nervous system, multiple sclerosis,AIDS-related neurodegeneration and Alzheimer's disease, infectiousmeningitis, encephalomyelitis, Parkinson's disease, Huntington'sdisease, amyotrophic lateral sclerosis and viral or autoimmuneencephalitis; autoimmune diseases, including Type I and Type II diabetesmellitus; diabetic complications, including, but not limited to,diabetic cataract, glaucoma, retinopathy, nephropathy (such asmicroaluminuria and progressive diabetic nephropathy), polyneuropathy,mononeuropathies, autonomic neuropathy, gangrene of the feet,atherosclerotic coronary arterial disease, peripheral arterial disease,nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems,and a skin or mucous membrane complication (such as an infection, a shinspot, a candidal infection or necrobiosis lipoidica diabeticorum);immune-complex vasculitis, and systemic lupus erythematosus (SLE);inflammatory disease of the heart, such as cardiomyopathy, ischemicheart disease hypercholesterolemia, and artherosclerosis; as well asvarious other diseases that can have significant inflammatorycomponents, including preeclampsia, chronic liver failure, brain andspinal cord trauma, and cancer. The Cycloheteroalkenyl Compounds canalso be used for inhibiting, treating, or preventing pain associatedwith inflammatory disease that can, for example, be a systemicinflammation of the body, exemplified by gram-positive or gram negativeshock, hemorrhagic or anaphylactic shock, or shock induced by cancerchemotherapy in response to pro-inflammatory cytokines, e.g., shockassociated with pro-inflammatory cytokines. Such shock can be induced,e.g., by a chemotherapeutic agent that is administered as a treatmentfor cancer.

The Cycloheteroalkenyl Compounds can be used to treat or prevent UI.Examples of UI treatable or preventable using the CycloheteroalkenylCompounds include, but are not limited to, urge incontinence, stressincontinence, overflow incontinence, neurogenic incontinence, and totalincontinence.

The Cycloheteroalkenyl Compounds can be used to treat or prevent anulcer. Examples of ulcers treatable or preventable using theCycloheteroalkenyl Compounds include, but are not limited to, a duodenalulcer, a gastric ulcer, a marginal ulcer, an esophageal ulcer, or astress ulcer.

The Cycloheteroalkenyl Compounds can be used to treat or prevent IBD,including Crohn's disease and ulcerative colitis.

The Cycloheteroalkenyl Compounds can be used to treat or prevent IBS.Examples of IBS treatable or preventable using the CycloheteroalkenylCompounds include, but are not limited to, spastic-colon-type IBS andconstipation-predominant IBS.

The Cycloheteroalkenyl Compounds can be used to treat or prevent anaddictive disorder, including but not limited to, an eating disorder, animpulse-control disorder, an alcohol-related disorder, anicotine-related disorder, an amphetamine-related disorder, acannabis-related disorder, a cocaine-related disorder, anhallucinogen-related disorder, an inhalant-related disorders, and anopioid-related disorder, all of which are further sub-classified aslisted below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; Anorexia; and EatingDisorder not otherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder with delusions, Alcohol Abuse,Alcohol Intoxication, Alcohol Withdrawal, Alcohol Intoxication Delirium,Alcohol Withdrawal Delirium, Alcohol-Induced Persisting Dementia,Alcohol-Induced Persisting Amnestic Disorder, Alcohol Dependence,Alcohol-Induced Psychotic Disorder with hallucinations, Alcohol-InducedMood Disorder, Alcohol-Induced Anxiety Disorder, Alcohol-Induced SexualDysfunction, Alcohol-Induced Sleep Disorder, and Alcohol-RelatedDisorder not otherwise specified (NOS).

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine-Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium,Amphetamine-Induced Psychotic Disorder with delusions,Amphetamine-Induced Psychotic Disorders with hallucinations,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder, and Amphetamine Related Disorder not otherwise specified(NOS).

Cannabis-related disorders include, but are not limited to, CannabisDependence, Cannabis Abuse, Cannabis Intoxication, Cannabis IntoxicationDelirium, Cannabis-Induced Psychotic Disorder with delusions,Cannabis-Induced Psychotic Disorder with hallucinations,Cannabis-Induced Anxiety Disorder, and Cannabis Related Disorder nototherwise specified (NOS).

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder withdelusions, Cocaine-Induced Psychotic Disorders with hallucinations,Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder,Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, andCocaine Related Disorder not otherwise specified (NOS).

Hallucinogen-related disorders include, but are not limited to,Hallucinogen Dependence, Hallucinogen Abuse, Hallucinogen Intoxication,Hallucinogen Withdrawal, Hallucinogen Intoxication Delirium,Hallucinogen Persisting Perception Disorder (Flashbacks),Hallucinogen-Induced Psychotic Disorder with delusions,Hallucinogen-Induced Psychotic Disorders with hallucinations,Hallucinogen-Induced Mood Disorder, Hallucinogen-Induced AnxietyDisorder, Hallucinogen-Induced Sexual Dysfunction, Hallucinogen-InducedSleep Disorder, and Hallucinogen Related Disorder not otherwisespecified (NOS).

Inhalant-related disorders include, but are not limited to, InhalantDependence, Inhalant Abuse, Inhalant Intoxication, Inhalant IntoxicationDelirium, Inhalant-Induced Psychotic Disorder with delusions,Inhalant-Induced Psychotic Disorder with hallucinations,Inhalant-Induced Anxiety Disorder, and Inhalant Related Disorder nototherwise specified (NOS).

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Withdrawal, Opioid Intoxication, OpioidIntoxication Delirium, Opioid-Induced Psychotic Disorder with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, and Opioid Related Disorder not otherwise specified(NOS).

The Cycloheteroalkenyl Compounds can be used to treat or preventParkinson's disease and parkinsonism and the symptoms associated withParkinson's disease and parkinsonism, including but not limited to,bradykinesia, muscular rigidity, resting tremor, and impairment ofpostural balance.

The Cycloheteroalkenyl Compounds can be used to treat or preventgeneralized anxiety or severe anxiety and the symptoms associated withanxiety, including but not limited to, restlessness; tension;tachycardia; dyspnea; depression, including chronic “neurotic”depression; panic disorder; agoraphobia and other specific phobias;eating disorders; and personality disorders.

The Cycloheteroalkenyl Compounds can be used to treat or preventepilepsy, including but not limited to, partial epilepsy, generalizedepilepsy, and the symptoms associated with epilepsy, including but notlimited to, simple partial seizures, jacksonian seizures, complexpartial (psychomotor) seizures, convulsive seizures (grand mal ortonic-clonic seizures), petit mal (absence) seizures, and statusepilepticus.

The Cycloheteroalkenyl Compounds can be used to treat or preventstrokes, including but not limited to, ischemic strokes and hemorrhagicstrokes.

The Cycloheteroalkenyl Compounds can be used to treat or prevent aseizure, including but not limited to, infantile spasms, febrileseizures, and epileptic seizures.

The Cycloheteroalkenyl Compounds can be used to treat or prevent apruritic condition, including but not limited to, pruritus caused by dryskin, scabies, dermatitis, herpetiformis, atopic dermatitis, pruritusvulvae et ani, miliaria, insect bites, pediculosis, contact dermatitis,drug reactions, urticaria, urticarial eruptions of pregnancy, psoriasis,lichen planus, lichen simplex chronicus, exfoliative dermatitis,folliculitis, bullous pemphigoid, or fiberglass dermatitis.

The Cycloheteroalkenyl Compounds can be used to treat or preventpsychosis, including but not limited to, schizophrenia, includingparanoid schizophrenia, hebephrenic or disorganized schizophrenia,catatonic schizophrenia, undifferentiated schizophrenia, negative ordeficit subtype schizophrenia, and non-deficit schizophrenia; adelusional disorder, including erotomanic subtype delusional disorder,grandiose subtype delusional disorder, jealous subtype delusionaldisorder, persecutory subtype delusional disorder, and somatic subtypedelusional disorder; and brief psychosis.

The Cycloheteroalkenyl Compounds can be used to treat or prevent acognitive disorder, including but not limited to, delirium and dementiasuch as multi-infarct dementia, dementia pugilistica, dementia caused byAIDS, and dementia caused by Alzheimer's disease.

The Cycloheteroalkenyl Compounds can be used to treat or prevent amemory deficiency, including but not limited to, dissociative amnesiaand dissociative fugue.

The Cycloheteroalkenyl Compounds can be used to treat or preventrestricted brain function, including but not limited to, that caused bysurgery or an organ transplant, restricted blood supply to the brain, aspinal cord injury, a head injury, hypoxia, cardiac arrest, orhypoglycemia.

The Cycloheteroalkenyl Compounds can be used to treat or preventHuntington's chorea.

The Cycloheteroalkenyl Compounds can be used to treat or prevent ALS.

The Cycloheteroalkenyl Compounds can be used to treat or preventretinopathy, including but not limited to, arteriosclerotic retinopathy,diabetic arteriosclerotic retinopathy, hypertensive retinopathy,non-proliferative retinopathy, and proliferative retinopathy.

The Cycloheteroalkenyl Compounds can be used to treat or prevent amuscle spasm.

The Cycloheteroalkenyl Compounds can be used to treat or prevent amigraine.

The Cycloheteroalkenyl Compounds can be used to treat or preventvomiting, including but not limited to, nausea vomiting, dry vomiting(retching), and regurgitation.

The Cycloheteroalkenyl Compounds can be used to treat or preventdyskinesia, including but not limited to, tardive dyskinesia and biliarydyskinesia.

The Cycloheteroalkenyl Compounds can be used to treat or preventdepression, including but not limited to, major depression and bipolardisorder.

Applicants believe that the Cycloheteroalkenyl Compounds are antagonistsfor VR1.

The invention also relates to methods for inhibiting VR1 function in acell comprising contacting a cell capable of expressing VR1 with aneffective amount of a Cycloheteroalkenyl Compound. This method can beused in vitro, for example, as an assay to select cells that express VR1and, accordingly, are useful as part of an assay to select compoundsuseful for treating or preventing pain, UI, an ulcer, IBD, or IBS. Themethod is also useful for inhibiting VR1 function in a cell in vivo, inan animal, a human in one embodiment, by contacting a cell, in ananimal, with an effective amount of a Cycloheteroalkenyl Compound. Inone embodiment, the method is useful for treating or preventing pain inan animal. In another embodiment, the method is useful for treating orpreventing UI in an animal. In another embodiment, the method is usefulfor treating or preventing an ulcer in an animal. In another embodiment,the method is useful for treating or preventing IBD in an animal. Inanother embodiment, the method is useful for treating or preventing IBSin an animal.

Examples of tissue comprising cells capable of expressing VR1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express VR1 are known in theart.

Applicants believe that the Cycloheteroalkenyl Compounds are antagonistsfor mGluR5.

The invention also relates to methods for inhibiting mGluR5 function ina cell comprising contacting a cell capable of expressing mGluR5 with anamount of a Cycloheteroalkenyl Compound effective to inhibit mGluR5function in the cell. This method can be used in vitro, for example, asan assay to select cells that express mGluR5 and, accordingly, areuseful as part of an assay to select compounds useful for treating orpreventing pain, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, a pruritic condition, or psychosis. The method isalso useful for inhibiting mGluR5 function in a cell in vivo, in ananimal, a human in one embodiment, by contacting a cell, in an animal,with an amount of a Cycloheteroalkenyl Compound effective to inhibitmGluR5 function in the cell. In one embodiment, the method is useful fortreating or preventing pain in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing an addictivedisorder in an animal in need thereof. In another embodiment, the methodis useful for treating or preventing Parkinson's disease in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing parkinsonism in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing anxiety inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing a pruritic condition in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing psychosis in an animal in need thereof.

Examples of cells capable of expressing mGluR5 are neuronal and glialcells of the central nervous system, particularly the brain, especiallyin the nucleus accumbens. Methods for assaying cells that express mGluR5are known in the art.

Applicants believe that the Cycloheteroalkenyl Compounds are antagonistsfor mGluR1.

The invention also relates to methods for inhibiting mGluR1 function ina cell comprising contacting a cell capable of expressing mGluR1 with anamount of a Cycloheteroalkenyl Compound effective to inhibit mGluR1function in the cell. This method can be used in vitro, for example, asan assay to select cells that express mGluR1 and, accordingly, areuseful as part of an assay to select compounds useful for treating orpreventing pain, UI, an addictive disorder, Parkinson's disease,parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruriticcondition, psychosis, a cognitive disorder, a memory deficit, restrictedbrain function, Huntington's chorea, ALS, dementia, retinopathy, amuscle spasm, a migraine, vomiting, dyskinesia, or depression. Themethod is also useful for inhibiting mGluR1 function in a cell in vivo,in an animal, a human in one embodiment, by contacting a cell, in ananimal, with an amount of a Cycloheteroalkenyl Compound effective toinhibit mGluR1 function in the cell. In one embodiment, the method isuseful for treating or preventing pain in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing UIin an animal in need thereof. In another embodiment, the method isuseful for treating or preventing an addictive disorder in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing Parkinson's disease in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventingparkinsonism in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing anxiety in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing epilepsy in an animal in need thereof. In another embodiment,the method is useful for treating or preventing stroke in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing a seizure in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a pruriticcondition in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing psychosis in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing a cognitive disorder in an animal in need thereof. Inanother embodiment, the method is useful for treating or preventing amemory deficit in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing restricted brain function inan animal in need thereof. In another embodiment, the method is usefulfor treating or preventing Huntington's chorea in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing ALS in an animal in need thereof. In another embodiment, themethod is useful for treating or preventing dementia in an animal inneed thereof. In another embodiment, the method is useful for treatingor preventing retinopathy in an animal in need thereof. In anotherembodiment, the method is useful for treating or preventing a musclespasm in an animal in need thereof. In another embodiment, the method isuseful for treating or preventing a migraine in an animal in needthereof. In another embodiment, the method is useful for treating orpreventing vomiting in an animal in need thereof. In another embodiment,the method is useful for treating or preventing dyskinesia in an animalin need thereof. In another embodiment, the method is useful fortreating or preventing depression in an animal in need thereof.

Examples of cells capable of expressing mOluRl include, but are notlimited to, cerebellar Purkinje neuron cells, Purkinje cell bodies(punctate), cells of spine(s) of the cerebellum; neurons and neurophilcells of olfactory-bulb glomeruli; cells of the superficial layer of thecerebral cortex; hippocampus cells; thalamus cells; superior colliculuscells; and spinal trigeminal nucleus cells. Methods for assaying cellsthat express mGluR1 are known in the art.

4.6 Therapeutic/Prophylactic Administration and Compositions of theInvention

Due to their activity, the Cycloheteroalkenyl Compounds areadvantageously useful in veterinary and human medicine. As describedabove, the Cycloheteroalkenyl Compounds are useful for treating orpreventing a condition in an animal in need thereof.

When administered to an animal, the Cycloheteroalkenyl Compounds areadministered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The presentcompositions, which comprise a Cycloheteroalkenyl Compound, can beadministered orally. The Cycloheteroalkenyl Compounds of the inventioncan also be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.)and can be administered together with another therapeutically activeagent. Administration can be systemic or local. Various delivery systemsare known, e.g., encapsulation in liposomes, microparticles,microcapsules, capsules, etc., and can be used to administer theCycloheteroalkenyl Compound.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of the Cycloheteroalkenyl Compounds into the bloodstream.

In specific embodiments, it can be desirable to administer theCycloheteroalkenyl Compounds locally. This can be achieved, for example,and not by way of limitation, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository orenema, or by means of an implant, said implant being of a porous,non-porous, or gelatinous material, including membranes, such assialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce theCycloheteroalkenyl Compounds into the central nervous system orgastrointestinal tract by any suitable route, includingintraventricular, intrathecal, and epidural injection, and enema.Intraventricular injection can be facilitated by an intraventricularcatheter, for example, attached to a reservoir, such as an Ommayareservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the Cycloheteroalkenyl Compounds can be formulatedas a suppository, with traditional binders and excipients such astriglycerides.

In another embodiment, the Cycloheteroalkenyl Compounds can be deliveredin a vesicle, in particular a liposome (see Langer, Science249:1527-1533 (1990) and Treat et al., Liposomes in the Therapy ofInfectious Disease and Cancer 317-327 and 353-365 (1989)).

In yet another embodiment, the Cycloheteroalkenyl Compounds can bedelivered in a controlled-release system or sustained-release system(see, e.g., Goodson, in Medical Applications of Controlled Release,supra, vol. 2, pp. 115-138 (1984)). Other controlled- orsustained-release systems discussed in the review by Langer, Science249:1527-1533 (1990) can be used. In one embodiment, a pump can be used(Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref. Biomed.Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); and Saudeket al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease (Langer and Wise eds., 1974); Controlled Drug Bioavailability,Drug Product Design and Performance (Smolen and Ball eds., 1984); Rangerand Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)). In yet anotherembodiment, a controlled- or sustained-release system can be placed inproximity of a target of the Cycloheteroalkenyl Compounds, e.g., thespinal column, brain, or gastrointestinal tract, thus requiring only afraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the animal.

Such pharmaceutical excipients can be liquids, such as water and oils,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical excipients can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipientsare sterile when administered to an animal. Water is a particularlyuseful excipient when the Cycloheteroalkenyl Compound is administeredintravenously. Saline solutions and aqueous dextrose and glycerolsolutions can also be employed as liquid excipients, particularly forinjectable solutions. Suitable pharmaceutical excipients also includestarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. The present compositions, if desired, can also containminor amounts of wetting or emulsifying agents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other fon suitable foruse. In one embodiment, the composition is in the form of a capsule (seee.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the Cycloheteroalkenyl Compounds are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. Compositions for oral delivery can be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions can contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these latter platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time-delay material such as glycerol monostearate orglycerol stearate can also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose, and magnesium carbonate. In oneembodiment, the excipients are of pharmaceutical grade.

In another embodiment, the Cycloheteroalkenyl Compounds can beformulated for intravenous administration. Typically, compositions forintravenous administration comprise sterile isotonic aqueous buffer.Where necessary, the compositions can also include a solubilizing agent.Compositions for intravenous administration can optionally include alocal anesthetic such as lidocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampule or sachette indicating the quantity of active agent. Wherethe Cycloheteroalkenyl Compounds are to be administered by infusion,they can be dispensed, for example, with an infusion bottle containingsterile pharmaceutical grade water or saline. Where theCycloheteroalkenyl Compounds are administered by injection, an ampule ofsterile water for injection or saline can be provided so that theingredients can be mixed prior to administration.

The Cycloheteroalkenyl Compounds can be administered bycontrolled-release or sustained-release means or by delivery devicesthat are known to those of ordinary skill in the art. Examples include,but are not limited to, those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595;5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566,each of which is incorporated herein by reference. Such dosage forms canbe used to provide controlled- or sustained-release of one or moreactive ingredients using, for example, hydropropylmethyl cellulose,other polymer matrices, gels, permeable membranes, osmotic systems,multilayer coatings, microparticles, liposomes, microspheres, or acombination thereof to provide the desired release profile in varyingproportions. Suitable controlled- or sustained-release formulationsknown to those of ordinary skill in the art, including those describedherein, can be readily selected for use with the active ingredients ofthe invention. The invention thus encompasses single unit dosage formssuitable for oral administration such as, but not limited to, tablets,capsules, gelcaps, and caplets that are adapted for controlled- orsustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained counterparts. In one embodiment, acontrolled- or sustained-release composition comprises a minimal amountof a Cycloheteroalkenyl Compound to cure or control the condition in aminimum amount of time. Advantages of controlled- or sustained-releasecompositions include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition, controlled- orsustained-release compositions can favorably affect the time of onset ofaction or other characteristics, such as blood levels of theCycloheteroalkenyl Compound, and can thus reduce the occurrence ofadverse side effects.

Controlled- or sustained-release compositions can initially release anamount of a Cycloheteroalkenyl Compound that promptly produces thedesired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the Cycloheteroalkenyl Compound tomaintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of theCycloheteroalkenyl Compound in the body, the Cycloheteroalkenyl Compoundcan be released from the dosage form at a rate that will replace theamount of Cycloheteroalkenyl Compound being metabolized and excretedfrom the body. Controlled- or sustained-release of an active ingredientcan be stimulated by various conditions, including but not limited to,changes in pH, changes in temperature, concentration or availability ofenzymes, concentration or availability of water, or other physiologicalconditions or compounds.

The amount of the Cycloheteroalkenyl Compound that is effective in thetreatment or prevention of a condition can be determined by standardclinical techniques. In addition, in vitro or in vivo assays canoptionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the Condition and can be decidedaccording to the judgment of a practitioner and/or each animal'scircumstances. Suitable effective dosage amounts, however, range fromabout 0.01 mg/kg of body weight to about 2500 mg/kg of body weight,although they are typically about 100 mg/kg of body weight or less. Inone embodiment, the effective dosage amount ranges from about 0.01 mg/kgof body weight to about 100 mg/kg of body weight of a CycloheteroalkenylCompound, in another embodiment, about 0.02 mg/kg of body weight toabout 50 mg/kg of body weight, and in another embodiment, about 0.025mg/kg of body weight to about 20 mg/kg of body weight. In oneembodiment, an effective dosage amount is administered about every 24 huntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 12 h until the Condition isabated. In another embodiment, an effective dosage amount isadministered about every 8 h until the Condition is abated. In anotherembodiment, an effective dosage amount is administered about every 6 huntil the Condition is abated. In another embodiment, an effectivedosage amount is administered about every 4 h until the Condition isabated. The effective dosage amounts described herein refer to totalamounts administered; that is, if more than one CycloheteroalkenylCompound is administered, the effective dosage amounts correspond to thetotal amount administered.

Where a cell capable of expressing VR1, mGluR5 or mGluR1 is contactedwith a Cycloheteroalkenyl Compound in vitro, the amount effective forinhibiting the VR1, mGluR5 or mGluR1 receptor function in a cell willtypically range from about 0.01 μg/L to about 5 mg/L, in one embodiment,from about 0.01 μg/L to about 2.5 mg/L, in another embodiment, fromabout 0.01 μg/L to about 0.5 mg/L, and in another embodiment, from about0.01 μg/L to about 0.25 mg/L of a solution or suspension of apharmaceutically acceptable carrier or excipient. In one embodiment, thevolume of solution or suspension comprising the CycloheteroalkenylCompound is from about 0.01 μL to about 1 mL. In another embodiment, thevolume of solution or suspension is about 200 μL.

Where a cell capable of expressing VR1, mGluR5, or mGluR1 is contactedwith a Cycloheteroalkenyl Compound in vivo, the amount effective forinhibiting the receptor function in a cell will typically range fromabout 0.01 mg/kg of body weight to about 2500 mg/kg of body weight,although it typically ranges from about 100 mg/kg of body weight orless. In one embodiment, the effective dosage amount ranges from about0.01 mg/kg of body weight to about 100 mg/kg of body weight of aCycloheteroalkenyl Compound, in another embodiment, about 0.020 mg/kg ofbody weight to about 50 mg/kg of body weight, and in another embodiment,about 0.025 mg/kg of body weight to about 20 mg/kg of body weight. Inone embodiment, an effective dosage amount is administered about every24 h. In another embodiment, an effective dosage amount is administeredabout every 12 h. In another embodiment, an effective dosage amount isadministered about every 8 h. In another embodiment, an effective dosageamount is administered about every 6 h. In another embodiment, aneffective dosage amount is administered about every 4 h.

The Cycloheteroalkenyl Compounds can be assayed in vitro or in vivo forthe desired therapeutic or prophylactic activity prior to use in humans.Animal model systems can be used to demonstrate safety and efficacy.

The present methods for treating or preventing a Condition in an animalin need thereof can further comprise administering to the animal beingadministered a Cycloheteroalkenyl Compound another therapeutic agent. Inone embodiment, the other therapeutic agent is administered in aneffective amount.

The present methods for inhibiting VR1 function in a cell capable ofexpressing VR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR5 function in a cell capable ofexpressing mGluR5 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

The present methods for inhibiting mGluR1 function in a cell capable ofexpressing mGluR1 can further comprise contacting the cell with aneffective amount of another therapeutic agent.

Effective amounts of the other therapeutic agents are known to thoseskilled in the art. However, it is within the skilled artisan's purviewto determine the other therapeutic agent's optimal effective-amountrange. In one embodiment of the invention, where another therapeuticagent is administered to an animal, the effective amount of theCycloheteroalkenyl Compound is less than its effective amount would bewhere the other therapeutic agent is not administered. In this case,without being bound by theory, it is believed that theCycloheteroalkenyl Compounds and the other therapeutic agent actsynergistically to treat or prevent a Condition.

The other therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroidal anti-inflammatoryagent, an antimigraine agent, a Cox-II inhibitor, an antiemetic, aβ-adrenergic blocker, an anticonvulsant, an antidepressant, aCa2+-channel blocker, an anticancer agent, an agent for treating orpreventing UI, an agent for treating or preventing an ulcer, an agentfor treating or preventing IBD, an agent for treating or preventing IBS,an agent for treating addictive disorder, an agent for treatingParkinson's disease and parkinsonism, an agent for treating anxiety, anagent for treating epilepsy, an agent for treating a stroke, an agentfor treating a seizure, an agent for treating a pruritic condition, anagent for treating psychosis, an agent for treating Huntington's chorea,an agent for treating ALS, an agent for treating a cognitive disorder,an agent for treating a migraine, an agent for inhibiting vomiting, anagent for treating dyskinesia, or an agent for treating depression, andmixtures thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazenefentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papavereturn, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable salts thereof, and mixturesthereof.

In certain embodiments, the opioid agonist is selected from codeine,hydromorphone, hydrocodone, oxycodone, dihydrocodeine, dihydromorphine,morphine, tramadol, oxymorphone, pharmaceutically acceptable saltsthereof, and mixtures thereof.

Examples of useful non-opioid analgesics include non-steroidalanti-inflammatory agents, such as aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, andpharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics include the following, non-limiting,chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs, see Paul A. Insel, Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout, inGoodman & Gilman's The Pharmacological Basis of Therapeutics 617-57(Perry B. Molinhoff and Raymond W. Ruddon eds., 9^(th) ed 1996) and GlenR. Hanson, Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II 1196-1221 (A. R.Gennaro ed. 19th ed. 1995) which are hereby incorporated by reference intheir entireties.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, rofecoxib andcelecoxib.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, and mixtures thereof.

The other therapeutic agent can also be an agent useful for reducing anypotential side effects of a Cycloheteroalkenyl Compounds. For example,the other therapeutic agent can be an antiemetic agent. Examples ofuseful antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, odansteron, granisetron, hydroxyzine,acetylleucine monoethanolamine, alizapride, azasetron, benzquinamide,bietanautine, bromopride, buclizine, clebopride, cyclizine,dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal,metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride,tetrahydrocannabinol, thiethylperazine, thioproperazine, tropisetron,and mixtures thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenyloin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenyloin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimelidine.

Examples of useful Ca2+-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, and perhexyline.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, fluorocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alpha-2a, interferonalpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozotocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,tirapazamine, toremifene citrate, trestolone acetate, triciribinephosphate, trimetrexate, trimetrexate glucuronate, triptorelin,tubulozole hydrochloride, uracil mustard, uredepa, vapreotide,verteporfin, vinblastine sulfate, vincristine sulfate, vindesine,vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride.

Examples of other anti-cancer drugs include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocaimycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;odansteron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxelderivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofuran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, and dicyclomine.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H₂antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; and antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazine;mesalamine; prednisone; azathioprine; mercaptopurine; and methotrexate.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropine methylbromide,and methantheline; and antidiarrheal drugs such as diphenoxylate andloperamide.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, and serotoninantagonists.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, and trihexyphenidylhydrochloride.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, temazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; andpropanediol carbamates, such as meprobamate and tybamate.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, γ-vinyl GABA, acetazolamide, andfelbamate.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, and acetylsalicylic acid.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenyloin, primidone, valproicacid, trimethadione, benzodiazepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, and felbamate.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; and antihistamines.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; and ziprasidone.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol andpimozide.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan and dantrolene.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; andantidepressant drugs such as those given below.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, sumatriptan; methysergide;ergotamine; caffeine; and beta-blockers such as propranolol, verapamil,and divalproex.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT₃ receptor antagonistssuch as odansteron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazin, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; and benzodiazepines such as lorazepam and alprazolam.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine and tetrabenazine.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotiline, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlafaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; and psychostimulants such as dextroamphetamine andmethylphenidate.

A Cycloheteroalkenyl Compound and the other therapeutic agent can actadditively or, in one embodiment, synergistically. In one embodiment, aCycloheteroalkenyl Compound is administered concurrently with anothertherapeutic agent; for example, a composition comprising an effectiveamount of a Cycloheteroalkenyl Compound and an effective amount ofanother therapeutic agent can be administered. Alternatively, acomposition comprising an effective amount of a CycloheteroalkenylCompound and a different composition comprising an effective amount ofanother therapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a Cycloheteroalkenyl Compound isadministered prior or subsequent to administration of an effectiveamount of another therapeutic agent. In this embodiment, theCycloheteroalkenyl Compound is administered while the other therapeuticagent exerts its therapeutic effect, or the other therapeutic agent isadministered while the Cycloheteroalkenyl Compound exerts itstherapeutic effect for treating or preventing a Condition.

A composition of the invention is prepared by a method comprisingadmixing a Cycloheteroalkenyl Compound or a pharmaceutically acceptablesalt and a pharmaceutically acceptable carrier or excipient. Admixingcan be accomplished using methods known for admixing a compound (orsalt) and a pharmaceutically acceptable carrier or excipient. In oneembodiment the Cycloheteroalkenyl Compound is present in the compositionin an effective amount.

4.7 Kits

The invention encompasses kits that can simplify the administration of aCycloheteroalkenyl Compound to an animal.

A typical kit of the invention comprises a unit dosage form of aCycloheteroalkenyl Compound. In one embodiment, the unit dosage form isa container, which can be sterile, containing an effective amount of aCycloheteroalkenyl Compound and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the Cycloheteroalkenyl Compound to treat aCondition. The kit can also further comprise a unit dosage form ofanother therapeutic agent, for example, a second container containing aneffective amount of the other therapeutic agent and a pharmaceuticallyacceptable carrier or excipient. In another embodiment, the kitcomprises a container containing an effective amount of aCycloheteroalkenyl Compound, an effective amount of another therapeuticagent and a pharmaceutically acceptable carrier or excipient. Examplesof other therapeutic agents include, but are not limited to, thoselisted above.

Kits of the invention can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, which would be within the purview of those skilled inthe art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES 5.1 Example 1 Synthesis of a Cycloheteroalkenyl CompoundJ37(c)

A solution of 4-tert-butyl phenyl isocyanate 22 (2.45 g, 14 mmol)(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) in DCM (7 mL) was added to a solution of1,4-dioxa-8-azaspiro[4,5]decane 21 (2 g, 14 mmol) (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) inDCM (7 mL) at about 25° C. and the resulting reaction mixture wasallowed to stir for 5 minutes. The solvent was removed under reducedpressure to provide a compound of formula 23. The compound of formula 23was dissolved in THF (20 mL) and 1N HCl in acetic acid (30 mL) was addedto the solution. The resulting reaction mixture was then heated atreflux temperature for about 3 h, cooled to about 25° C., and thesolvent removed under reduced pressure to provide a residue. Theresulting residue was dissolved in DCM, neutralized with saturatedaqueous Na₂CO₃ solution, and the organic layer separated from theaqueous layer. The aqueous layer was then extracted three times with DCMand the DCM layers combined. The combined DCM layers were dried (MgSO₄)and the DCM removed under reduced pressure to provide a compound offormula 24. The compound of formula 24 was purified by columnchromatography using a silica gel column eluted with hexane/ethylacetate (1:1). The compound of formula 24 was obtained as a white solid(1.6 g, 42% yield).

The compound of formula 24 (1 g, 3.64 mmol) was dissolved in THF (100mL) and the resulting solution cooled to about −78° C. To the cooledsolution was then added a 1M solution of LiHMDS in THF (8.75 ml, 8.75mmol) and the resulting reaction mixture was allowed to stir at about−78° C. for about 2 h. After stirring for 2 h, of2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine 5(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) (1.43 g, 3.64 mmol), dissolved in about 5 mL ofTHF at −78° C., was added to the reaction mixture and the reactionmixture was allowed to stir at −78 C for another 2 h. The reactionmixture was then allowed to warm to about 25° C. and the solvent wasremoved under reduced pressure to provide a residue. The resultingresidue was purified by column chromatography using a silica gel columneluted with hexane/ethyl acetate (5:1) to provide a compound of formula25 as white solids (0.9 g, 62% yield).

The compound of formula 25, (0.9 g, 2.21 mmol) and palladiumtetrakistriphenylphosphine (Pd(PPh₃)₄) (128 mg, 0.111 mmol) weredissolved in THF (50 ml) and 0.5 M solution of a compound of3-methyl-2-pyridylzinc bromide 26 in THF (13.3 ml, 6.64 mmol)(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) was added to the reaction mixture. The reactionmixture was heated at reflux temperature for about 1 h, cooled to about25° C., and the solvent removed under reduced pressure to provide aresidue. The resulting residue was purified by column chromatographyusing a silica gel column eluted with hexane/ethyl acetate (1:1) toprovide Compound J37(c). Compound J37(c) was then further purified bytrituation with ethyl acetate to provide Compound J37(c) as a whitesolid (490 mg, 63%).

The identity of Compound J37(c) was confirmed using ¹H-NMR spectroscopy.

Compound J37(c): ¹H-NMR (CDCl₃): δ 1.31 (9H, s), 2.36 (3H, s), 2.64 (2H,br), 3.77 (2H, m), 4.19 (2H, m), 5.85 (1H, m), 6.48 (1H, s), 7.13 (1H,m), 7.33 (4H, dd), 7.52 (1H, m), 8.44 (1H, m).

5.2 Example 2 Synthesis of a Cycloheteroalkenyl Compound J39(c)

A solution of 4-iso-propyl phenyl isocyanate 27 (2.25 g, 14 mmol)(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) in DCM (7 mL) was added to a solution of1,4-dioxa-8-azaspiro[4,5]decane 21 (2 g, 14 mmol) (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) inDCM (7 mL) at about 25° C. and the resulting reaction mixture wasallowed to stir for 5 minutes. The solvent was removed under reducedpressure to provide a compound of formula 28. The compound of formula 28was dissolved in DCM (30 mL) and trifluoroacetic acid (15 mL) was addedto the solution. The resulting reaction mixture was then heated atreflux temperature for about 5 hours, cooled to about 25° C., and thesolvent removed under reduced pressure to provide a residue. Theresulting residue was dissolved in DCM, neutralized with saturatedaqueous Na₂CO₃ solution, and the organic layer separated from theaqueous layer. The aqueous layer was then extracted three times with DCMand the DCM layers combined. The combined DCM layers were dried (MgSO₄)and the DCM removed under reduced pressure to provide a compound offormula 29 as a white solid (3.6 g, quantitative yield).

The compound of formula 29 (1.5 g, 5.76 mmol) was dissolved in THF (100mL) and the resulting solution cooled to about −78° C. To the cooledsolution was then added a 1M solution of LiHMDS in THF (13.8 ml, 13.8mmol) and the resulting reaction mixture was allowed to stir at about−78° C. for about 2 hours. After stirring for 2 h,2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine 5 (2.26 g,5.76 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)), dissolved in about 5 mL of THF at −78° C., wasadded to the reaction mixture and the reaction mixture was allowed tostir at −78° C. for another 2 h. The reaction mixture was then allowedto warm to about 25° C. and the solvent was removed under reducedpressure to provide a residue. The resulting residue was purified byflash column chromatography using a silica gel column eluted with anhexane/ethyl acetate gradient (12:1 to 6:1) to provide a compound offormula 30 as yellow oil (0.5 g, 22% yield).

The compound of formula 30, (0.5 g, 1.25 mmol) and Pd(PPh₃)₄ (72.2 mg,0.063 mmol) were dissolved in THF (20 mL) and 0.5 M solution of3-methyl-2-pyridylzinc bromide 26 in THF (7.5 ml, 3.75 mmol)(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) was added to the reaction mixture. The reactionmixture was heated at reflux temperature for about 1 h, cooled to about25° C., and the solvent removed under reduced pressure to provide aresidue. The resulting residue was purified by column chromatographyusing a silica gel column eluted with hexane/ethyl acetate (1:3) toprovide Compound J39(c). Compound J39(c) was then further purified bytrituation with diethylether followed by preparative thin-layerchromatography (silica gel eluted with hexane/ethyl acetate (1:1)) toprovide Compound J39(c) as a white solid (20 mg, 5%).

The identity of Compound J39(c) was confirmed using ¹H-NMR spectroscopy.

Compound J39(c): ¹H-NMR (CDCl₃):

1.25 (6H, d, J=6.7 Hz), 2.37 (3H, s), 2.66 (2H, m), 2.89 (1H, m), 3.78(2H, t, J=11.2 Hz), 4.20 (2H, dd, J=2.7, 3 Hz), 5.86 (1H, m), 6.38 (1H,s), 7.13 (1H, dd, J=4.9, 7.9 Hz), 7.18 (2H, m), 7.32 (2H, m), 7.53 (1H,m), 8.45 (1H, m).

5.3 Example 3 Synthesis of a Cycloheteroalkenyl Compound J44(c)

A solution of 4-trifluoromethylphenyl isocyanate 31 (6.86 g)(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) was added in one portion to a solution of1,4-dioxa-8-azaspiro[4,5]decane 21 (5 g) (commercially available fromSigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)) in DCM (40 mL) atabout 25° C. and the resulting reaction mixture was allowed to stir forabout 2 h. The solvent was removed under reduced pressure to provide acompound of formula 32. The compound of formula 32 was dissolved in THF(100 mL) and 2N HCl (100 mL) was added to the solution. The resultingreaction mixture was then heated at about 50° C. for about 4 h andcooled to about 25° C. The aqueous and organic layers were thenseparated, the aqueous layer was extracted with ethyl acetate (100 mL),and the organic layers were combined. The combined organic layers werethen dried (MgSO₄) and the solvent removed under reduced pressure toprovide a residue. The residue was purified by column chromatographyusing a silica gel column eluted with hexane/ethyl acetate (1:1) toprovide the compound of formula 33 (2.71 g).

The compound of formula 33 (1.03 g) was dissolved in THF (50 mL) and theresulting solution cooled to about −78° C. To the cooled solution wasthen added a 1M solution of LiHMDS in THF (9 mL) and the resultingreaction mixture was allowed to stir at about −78° C. for about 1 hour.After stirring for 1 h.,2-[N,N-bis(trifluoromethylsulfonyl)amino]-5-chloropyridine 5 (1.7 g,)(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) in 20 mL of THF was added dropwise to thereaction mixture over a period of about 20 minutes. The solvent wasremoved under reduced pressure to provide a residue. The resultingresidue was purified by column chromatography using a silica gel columneluted with hexane/ethyl acetate (1:1) to provide a compound of formula34 as white solids (0.9 g).

The compound of formula 34, (2.3 g) in THF (30 mL) was added in oneportion to Pd(PPh₃)₄ (318 mg) in THF (70 mL) followed by3-methyl-2-pyridylzinc bromide 26 (33 ml, 0.5 M in THF) (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com)).The resulting reaction mixture was heated at reflux temperature forabout 3 h, cooled to about 25° C., and the solvent removed under reducedpressure to provide a residue. The residue was dissolved in ethylacetate and washed with saturated aqueous sodium bicarbonate (2×100 mL)and water (100 mL). The ethyl acetate was then dried (Na₂SO₄) and thesolvent removed under reduced pressure to provide a residue. Theresulting residue was purified by column chromatography using a silicagel column eluted with hexane/ethyl acetate (1:2) to provide CompoundJ44(c) (1.8 g).

The identity of Compound J44(c) was confirmed using ¹H-NMR spectroscopyand mass spectrometry.

Compound J44(c): ¹H NMR (400 MHz, CDCl₃) δ 8.44 (1H, dd, J4.7 and 1.1Hz), 7.57-7.52 (5H, m), 7.13 (1H, dd, J7.7 and 4.7 Hz), 6.62 (1H, s),5.87-5.85 (1H, m), 4.22 (2H, q, J2.7 Hz), 3.79 (2H, t, J5.6 Hz),2.68-2.65 (2H, m) and 2.36 (3H, s).

MS (ES+) 362 (M+H)⁺.

5.4 Example 4 Synthesis of a Cycloheteroalkenyl Compound I14(c)

6-Methyl-2-amino-benzothiazole 35 (10 g, 60.89 mmol) (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com))was dissolved in DMF (100 mL) and cooled to about 0° C. under a nitrogenatmosphere. To the resulting solution was added 1,1-carbonyldiimidazole36 (11.1 g, 66.98 mmol) (commercially available from Sigma-Aldrich, St.Louis, Mo. (www.sigma-aldrich.com)) and the resulting reaction mixturewas stirred for about 1 h at about 0° C. The reaction mixture was thenallowed to warm to about 25° C. over about 3 hours. The reaction mixturewas diluted with acetone (100 mL) and filtered to provide the acylimidazolide 37 (13.2 g, 84%) as a white solid. The acyl imidazolide 37was suspended in dry DMF (100 mL) under a nitrogen atmosphere and1,4-dioxa-8-azaspiro[4.5]decane 21 (7.32 g, 51.1 mmol) (commerciallyavailable from Sigma-Aldrich, St. Louis, Mo. (www.sigma-aldrich.com))was added to the suspension and the resulting reaction mixture heated toabout 100° C. for about 1 h. The solvent was then removed under reducedpressure to provide a residue. To the resulting residue was added 250 mLof a 1M sodium carbonate solution and the resulting mixture stirredvigorously for about 1 h. After stirring the reaction mixture wasfiltered to provide a solid that was washed with water (100 mL) anddried under reduced pressure to provide a compound of formula 38 as awhite solid (16 g, 79%).

The compound of formula 38 (25.9 g, 77.68 mmol) was suspended in ethylacetate (200 mL) and a 1:1 mixture of concentrated HCl and ethyl acetate(50 mL) was added to the solution. The resulting reaction mixture washeated at about 60° C. for about 1 h. The reaction mixture was thencooled to about 25° C. and partitioned between ethyl acetate (600 mL)and 2M potassium carbonate (600 mL). The organic phase was separated,dried (MgSO₄), and the solvent removed under reduced pressure. Theresulting solid was purified by column chromatography using a silica gelcolumn eluted with DCM:methanol (50:1) to provide a compound of formula39 as a white solid (12.4 g, 55%).

The compound of formula 39 (4.00 g, 13.82 mmol) was dissolved in dry THF1(50 mL) and cooled to about −78° C. under an argon atmosphere. A 1 Msolution of LiHMDS in THF (34.55 ml, 34.55 mmol) was added via syringeto the resulting solution and the resulting reaction mixture was stirredat about −78° C. for about 2 h. After stirring,2-[N,N-bis)trifluoromethylsulphonyl)amino]-5-chloropyridine 5(commercially available from Sigma-Aldrich, St. Louis, Mo.(www.sigma-aldrich.com)) in THF (25 mL) was added dropwise to thereaction mixture, the reaction mixture was allowed to warm to about 25°C., and was stirred for about 18 h. The solvent was then removed underreduced pressure to provide a residue that was purified by columnchromatography using a silica gel column eluted with ethylacetate:hexanes (1:4) to provide a compound of formula 40 (4.6 g,79.0%).

The compound of formula 40 (2.2 g, 5.22 mmol), 3-methyl-pyridin-2-ylzinc bromide 26 (4.4 g, 18.42 mmol), and Pd(PPh₃)₄ (0.355 g, 0.307 mmol)were dissolved in THF (80 mL) and the resulting reaction mixture washeated at reflux temperature for about 18 h. The reaction mixture wascooled to about 25° C. and partitioned between ethyl acetate (300 mL)and saturated brine solution (300 mL). The organic layer was separated,dried (MgSO₄), and the solvent removed under reduced pressure to providea residue. The residue was purified by column chromatography using asilica gel column eluted with ethyl acetate:hexanes (2:3) to provideCompound I141(c) as a white solid (1.1 g, 57%).

5.5 Example 5 Synthesis of a Cycloheteroalkenyl Compound I40(c)

Compound I40(c) was obtained by a method analogous to that used toobtain Compound I41(c), as described above in Example 4, except that6-fluoro-2-amino-benzothiazole was used in place of6-methyl-2-amino-benzothiazole.

5.6 Example 6 Binding of Cycloheteroalkenyl Compounds to mGluR5

The following assay can be used to demonstrate that CycloheteroalkenylCompounds bind to mGluR5 and, accordingly, are useful for treating orpreventing, e.g., pain.

Cell Cultures:

Primary glial cultures are prepared from cortices of Sprague-Dawley 18days old embryos. The cortices are dissected and then dissociated bytrituration. The resulting cell homogenate is plated onto poly-D-lysineprecoated T175 flasks (BIOCOAT, commercially available from BectonDickinson and Company, Inc. of Franklin Lakes, N.J.) in Dulbecco'sModified Eagle's Medium (“DMEM,” pH 7.4), buffered with 25 mM HEPES, andsupplemented with 15% fetal calf serum (“FCS,” commercially availablefrom Hyclone Laboratories Inc. of Omaha, Nebr.), and incubated at 37° C.and 5% CO₂. After 24 hours, FCS supplementation is reduced to 10%. Onday six, oligodendrocytes and microglia are removed by strongly tappingthe sides of the flasks. One day following this purification step,secondary astrocyte cultures are established by subplating onto 96poly-D-lysine precoated T175 flasks (BIOCOAT) at a density of 65,000cells/well in DMEM and 10% FCS. After 24 hours, the astrocytes arewashed with serum free medium and then cultured in DMEM, withoutglutamate, supplemented with 0.5% FCS, 20 mM HEPES, 10 ng/mL epidermalgrowth factor (“EGF”), 1 mM sodium pyruvate, and 1×penicillin/streptomycin at pH 7.5 for 3 to 5 days at 37° C. and 5% CO₂.The procedure allows the expression of the mGluR5 receptor byastrocytes, as demonstrated by S. Miller et al., J. Neuroscience15(9):6103-6109 (1995).

Assay Protocol:

After 3-5 days incubation with EGF, the astrocytes are washed with 127mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 mM NaH₂PO₄, 2 mM CaCl₂, 5 mM NaHCO₃,8 mM HEPES, 10 mM Glucose at pH 7.4 (“Assay Buffer”) and loaded with thedye Fluo-4 (commercially available from Molecular Probes Inc. of Eugene,Oreg.) using 0.1 mL of Assay Buffer containing Fluo-4 (3 mM final).After 90 minutes of dye loading, the cells are then washed twice with0.2 mL Assay Buffer and resuspended in 0.1 mL of Assay Buffer. Theplates containing the astrocytes are then transferred to a FluorometricImaging Plate reader (“FLIPR,” commercially available from MolecularDevices Corporation of Sunnyvale, Calif.) for the assessment of calciummobilization flux in the presence of glutamate and in the presence orabsence of antagonist. After monitoring fluorescence for 15 seconds toestablish a baseline, DMSO solutions containing various concentrationsof a Cycloheteroalkenyl Compound diluted in Assay Buffer (0.05 mL of 4×dilutions for competition curves) are added to the cell plate andfluorescence is monitored for 2 minutes. 0.05 mL of a 4× glutamatesolution (agonist) is then added to each well to provide a finalglutamate concentration in each well of 10 mM. Plate fluorescence isthen monitored for an additional 60 seconds after agonist addition. Thefinal DMSO concentration in the assay is 1.0%. In each experiment,fluorescence is monitored as a function of time and the data analyzedusing Microsoft Excel and GraphPad Prism. Dose-response curves are fitusing a non-linear regression to determine the IC₅₀ value. In eachexperiment, each data point is determined two times.

5.7 Example 7 In Vivo Assays for Prevention or Treatment of Pain

Test Animals:

Each experiment uses rats weighing between 200-260 g at the start of theexperiment. The rats are group-housed and have free access to food andwater at all times, except prior to oral administration of aCycloheteroalkenyl Compound when food is removed for 16 hours beforedosing. A control group acts as a comparison to rats treated with aCycloheteroalkenyl Compound. The control group is administered thecarrier for the Cycloheteroalkenyl Compound. The volume of carrieradministered to the control group is the same as the volume of carrierand Cycloheteroalkenyl Compound administered to the test group.

Acute Pain:

To assess the actions of the Cycloheteroalkenyl Compounds for thetreatment or prevention of acute pain the rat tail flick test can beused. Rats are gently restrained by hand and the tail exposed to afocused beam of radiant heat at a point 5 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 20 seconds are removed from the tail flick unit andassigned a withdrawal latency of 20 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 5 hoursfollowing administration of a Cycloheteroalkenyl Compound. Data areexpressed as tail flick latency(s) and the percentage of the maximalpossible effect (% MPE), i.e., 20 seconds, is calculated as follows:

${\% \mspace{14mu} M\; P\; E} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} {latency}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \right\rbrack}{\left( {20\mspace{14mu} s\mspace{14mu} {pre}\text{-}{administration}\mspace{14mu} {latency}} \right)} \times 100}$

The rat tail flick test is described in F. E. D'Amour et al., “A Methodfor Determining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther.72:74-79 (1941).

Acute pain can also be assessed by measuring the animal's response tonoxious mechanical stimuli by determining the paw withdrawal threshold(“PWT”), as described below.

Inflammatory Pain:

To assess the actions of the Cycloheteroalkenyl Compounds for thetreatment or prevention of inflammatory pain the Freund's completeadjuvant (“FCA”) model of inflammatory pain is used. FCA-inducedinflammation of the rat hind paw is associated with the development ofpersistent inflammatory mechanical hyperalgesia and provides reliableprediction of the anti-hyperalgesic action of clinically usefulanalgesic drugs (L. Bartho et al., “Involvement of Capsaicin-sensitiveNeurones in Hyperalgesia and Enhanced Opioid Antinociception inInflammation,” Naunyn-Schmiedeberg's Archives of Pharmacol. 342:666-670(1990)). The left hind paw of each animal is administered a 50 μLintraplantar injection of 50% FCA. 24 hour post injection, the animal isassessed for response to noxious mechanical stimuli by determining thePWT, as described below. Rats are then administered a single injectionof 1, 3, 10 or 30 mg/Kg of either a Cycloheteroalkenyl Compound; 30mg/Kg of a control selected from Celebrex, indomethacin or naproxen; orcarrier. Responses to noxious mechanical stimuli are then determined 1,3, 5 and 24 hours post administration. Percentage reversal ofhyperalgesia for each animal is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack} \times 100}$

Neuropathic Pain:

To assess the actions of the Cycloheteroalkenyl Compounds for thetreatment or prevention of neuropathic pain either the Seltzer model orthe Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain is used to produce neuropathic hyperalgesia in rats (Z.Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve is performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the rat is shaved and the sciatic nerve exposed athigh thigh level through a small incision and is carefully cleared ofsurrounding connective tissues at a site near the trocanther just distalto the point at which the posterior biceps semitendinosus nerve branchesoff of the common sciatic nerve. A 7-0 silk suture is inserted into thenerve with a ⅜ curved, reversed-cutting mini-needle and tightly ligatedso that the dorsal ⅓ to ½ of the nerve thickness is held within theligature. The wound is closed with a single muscle suture (4-0 nylon(Vicryl)) and vetbond tissue glue. Following surgery, the wound area isdusted with antibiotic powder. Sham-treated rats undergo an identicalsurgical procedure except that the sciatic nerve is not manipulated.Following surgery, animals are weighed and placed on a warm pad untilthey recover from anesthesia. Animals are then returned to their homecages until behavioral testing begins. The animal is assessed forresponse to noxious mechanical stimuli by determining PWT, as describedbelow, prior to surgery (baseline), then immediately prior to and 1, 3,and 5 hours after drug administration for rear paw of the animal.Percentage reversal of neuropathic hyperalgesia is defined as:

${\% \mspace{14mu} {Reversal}} = {\frac{\left\lbrack {\left( {{post}\mspace{14mu} {administration}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack}{\left\lbrack {\left( {{baseline}\mspace{14mu} P\; W\; T} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu} P\; W\; T} \right)} \right\rbrack} \times 100}$

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then be returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a CycloheteroalkenylCompound for the left rear paw of the animal. The animal can also beassessed for response to noxious thermal stimuli or for tactileallodynia, as described below. The Chung model for neuropathic pain isdescribed in S. H. Kim, “An Experimental Model for Peripheral NeuropathyProduced by Segmental Spinal Nerve Ligation in the Rat,” Pain50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia:

The paw pressure assay can be used to assess mechanical hyperalgesia.For this assay, hind paw withdrawal thresholds (PWT) to a noxiousmechanical stimulus are determined using an analgesymeter (Model 7200,commercially available from Ugo Basile of Italy) as described in C.Stein, “Unilateral Inflammation of the Hindpaw in Rats as a Model ofProlonged Noxious Stimulation: Alterations in Behavior and NociceptiveThresholds,” Pharmacol. Biochem. and Behavior 31:451-455 (1988). Themaximum weight that can be applied to the hind paw is set at 250 g andthe end point is taken as complete withdrawal of the paw. PWT isdeteiniined once for each rat at each time point and only the affected(ipsilateral) paw is tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:

The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by K. Hargreaveset al., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Only theaffected (ipsilateral) paw is tested.

Assessment of Tactile Allodynia:

To assess tactile allodynia, rats are placed in clear, plexiglasscompartments with a wire mesh floor and allowed to habituate for aperiod of at least 15 minutes. After habituation, a series of von Freymonofilaments are presented to the plantar surface of the left(operated) foot of each rat. The series of von Frey monofilamentsconsists of six monofilaments of increasing diameter, with the smallestdiameter fiber presented first. Five trials are conducted with eachfilament with each trial separated by approximately 2 minutes. Eachpresentation lasts for a period of 4-8 seconds or until a nociceptivewithdrawal behavior is observed. Flinching, paw withdrawal or licking ofthe paw are considered nociceptive behavioral responses.

5.8 Example 8 In Vivo Assays for Prevention or Treatment of Anxiety

The elevated plus maze test or the shock-probe burying test can be usedto assess the anxiolytic activity of Cycloheteroalkenyl Compounds inrats or mice,

The Elevated Plus Maze Test:

The elevated plus maze consists of a platform with 4 arms, two open andtwo closed (50×10×50 cm enclosed with an open roof). Rats (or mice) areplaced in the center of the platform, at the crossroad of the 4 arms,facing one of the closed arms. Time spent in the open arms vs the closedarms and number of open arm entries during the testing period arerecorded. This test is conducted prior to drug administration and againafter drug administration. Test results are expressed as the mean timespent in open arms and the mean number of entries into open arms. Knownanxiolytic drugs increase both the time spent in open arms and number ofopen arm entries. The elevated plus maze test is described in D. Treit,“Animal Models for the Study of Anti-anxiety Agents: A Review,”Neuroscience & Biobehavioral Reviews 9(2):203-222 (1985).

The Shock-Probe Burying Test:

For the shock-probe burying test the testing apparatus consists of aplexiglass box measuring 40×30×40 cm, evenly covered with approximately5 cm of bedding material (odor absorbent kitty litter) with a small holein one end through which a shock probe (6.5 cm long and 0.5 cm indiameter) is inserted. The plexiglass shock probe is helically wrappedwith two copper wires through which an electric current is administered.The current is set at 2 mA. Rats are habituated to the testing apparatusfor 30 min on 4 consecutive days without the shock probe in the box. Ontest day, rats are placed in one corner of the test chamber followingdrug administration. The probe is not electrified until the rat touchesit with its snout or fore paws, at which point the rat receives a brief2 mA shock. The 15 min testing period begins once the rat receives itsfirst shock and the probe remains electrified for the remainder of thetesting period. The shock elicits burying behavior by the rat. Followingthe first shock, the duration of time the rat spends spraying beddingmaterial toward or over the probe with its snout or fore paws (buryingbehavior) is measured as well as the number of contact-induced shocksthe rat receives from the probe. Known anxiolytic drugs reduce theamount of burying behavior. In addition, an index of the rat'sreactivity to each shock is scored on a 4 point scale. The total timespent immobile during the 15 min testing period is used as an index ofgeneral activity. The shock-probe burying test is described in D. Treit,1985, supra.

5.9 Example 9 In Vivo Assays for Prevention or Treatment of an AddictiveDisorder

The conditioned place preference test or drug self-administration testcan be used to assess the ability of Cycloheteroalkenyl Compounds toattenuate the rewarding properties of known drugs of abuse.

The Conditioned Place Preference Test:

The apparatus for the conditioned place preference test consists of twolarge compartments (45×45×30 cm) made of wood with a plexiglass frontwall. These two large compartments are distinctly different. Doors atthe back of each large compartment lead to a smaller box (36×18×20 cm)box made of wood, painted grey, with a ceiling of wire mesh. The twolarge compartments differ in terms of shading (white vs black), level ofillumination (the plexiglass door of the white compartment is coveredwith aluminum foil except for a window of 7×7 cm), texture (the whitecompartment has a 3 cm thick floor board (40×40 cm) with nine equallyspaced 5 cm diameter holes and the black has a wire mesh floor), andolfactory cues (saline in the white compartment and 1 mL of 10% aceticacid in the black compartment). On habituation and testing days, thedoors to the small box remain open, giving the rat free access to bothlarge compartments.

The first session that a rat is placed in the apparatus is a habituationsession and entrances to the smaller grey compartment remain open givingthe rat free access to both large compartments. During habituation, ratsgenerally show no preference for either compartment. Followinghabituation, rats are given 6 conditioning sessions. Rats are dividedinto 4 groups: carrier pre-treatment+carrier (control group),Cycloheteroalkenyl Compound pre-treatment+carrier, carrierpre-treatment+morphine, Cycloheteroalkenyl Compoundpre-treatment+morphine. During each conditioning session the rat isinjected with one of the drug combinations and confined to onecompartment for 30 min. On the following day, the rat receives acarrier+carrier treatment and is confined to the other largecompartment. Each rat receives three conditioning sessions consisting of3 drug combination-compartment and 3 carrier-compartment pairings. Theorder of injections and the drug/compartment pairings arecounterbalanced within groups. On the test day, rats are injected priorto testing (30 min to 1 hour) with either morphine or carrier and therat is placed in the apparatus, the doors to the grey compartment remainopen and the rat is allowed to explore the entire apparatus for 20 min.The time spent in each compartment is recorded. Known drugs of abuseincrease the time spent in the drug-paired compartment during thetesting session. If the Cycloheteroalkenyl Compound blocks theacquisition of morphine conditioned place preference (reward), therewill be no difference in time spent in each side in rats pre-treatedwith a Cycloheteroalkenyl Compound and the group will not be differentfrom the group of rats that was given carrier+carrier in bothcompartments. Data will be analyzed as time spent in each compartment(drug combination-paired vs carrier-paired). Generally, the experimentis repeated with a minimum of 3 doses of a Cycloheteroalkenyl Compound.

The Drug Self-Administration Test:

The apparatus for the drug self-administration test is a standardcommercially available operant conditioning chamber. Before drug trialsbegin rats are trained to press a lever for a food reward. After stablelever pressing behavior is acquired, rats are tested for acquisition oflever pressing for drug reward. Rats are implanted with chronicallyindwelling jugular catheters for i.v. administration of compounds andare allowed to recover for 7 days before training begins. Experimentalsessions are conducted daily for 5 days in 3 hour sessions. Rats aretrained to self-administer a known drug of abuse, such as morphine. Ratsare then presented with two levers, an “active” lever and an “inactive”lever. Pressing of the active lever results in drug infusion on a fixedratio 1 (FR1) schedule (i.e., one lever press gives an infusion)followed by a 20 second time out period (signaled by illumination of alight above the levers). Pressing of the inactive lever results ininfusion of excipient. Training continues until the total number ofmorphine infusions stabilizes to within ±10% per session. Trained ratsare then used to evaluate the effect of Cycloheteroalkenyl Compoundspre-treatment on drug self-administration. On test day, rats arepre-treated with a Cycloheteroalkenyl Compound or excipient and then areallowed to self-administer drug as usual. If the CycloheteroalkenylCompound blocks the rewarding effects of morphine, rats pre-treated withthe Cycloheteroalkenyl Compound will show a lower rate of respondingcompared to their previous rate of responding and compared to excipientpre-treated rats. Data is analyzed as the change in number of druginfusions per testing session (number of infusions during testsession−number of infusions during training session).

5.10 Example 10 Functional Assay for Characterizing mGluR1 AntagonisticProperties

Functional assays for the characterization of mGluR 1 antagonisticproperties are known in the art. For example, the following procedurecan be used.

A CHO-rat mGluR1 cell line is generated using cDNA encoding rat mGluR1receptor (M. Masu and S, Nakanishi, Nature 349:760-765 (1991)). The cDNAencoding rat mGluR1 receptor can be obtained from, e.g., Prof. S,Nakanishi (Kyoto, Japan).

40,000 CHO-rat mGluR1 cells/well are plated into a COSTAR 3409, black,clear bottom, 96 well, tissue culture treated plate (commerciallyavailable from Fisher Scientific of Chicago, Ill.) and are incubated inDulbecco's Modified Eagle's Medium (DMEM, pH 7.4) supplemented withglutamine, 10% FBS, 1% Pen/Strep, and 500 μg/mL Geneticin for about 12h. The CHO-rat mGluR1 cells are then washed and treated with OPTIMEMmedium (commercially available from Invitrogen, Carlsbad, Calif.) andincubated for a time period ranging from 1 to 4 hours prior to loadingthe cells with the dye FLUO-4 (commercially available from MolecularProbes Inc., Eugene, Oreg.). After incubation, the cell plates arewashed with loading buffer (127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 700 μM,NaH₂PO₄, 2 mM CaCl₂, 5 mMNaHCO₃, 8 mM HEPES, and 10 mM glucose, pH 7.4)and incubated with 3 μM FLUO-4 in 0.1 mL loading buffer for 90 min. Thecells are then washed twice with 0.2 mL loading buffer, resuspended in0.1 mL of loading buffer, and transferred to a FLIPR for measurement ofcalcium mobilization flux in the presence of glutamate and in thepresence or absence of a Cycloheteroalkenyl Compound.

To measure calcium mobilization flux, fluoresence is monitored for about15 s to establish a baseline and DMSO solutions containing variousconcentrations of a Cycloheteroalkenyl Compound ranging from about 50 μMto about 0.8 nM diluted in loading buffer (0.05 mL of a 4× dilution) areadded to the cell plate and fluoresence is monitored for about 2 min.0.05 mL of a 4× glutamate solution (agonist) is then added to each wellto provide a final glutamate concentration in each well of 10 μM andfluoresence is monitored for about 1 additional min. The final DMSOconcentration in the assay is 1%. In each experiment fluoresence ismonitored as a function of time and the data is analyzed using anon-linear regression to determine the IC₅₀ value. In each experimenteach data point is determined twice.

5.11 Example 11 Binding of Cycloheteroalkenyl Compounds to VR1

Methods for assaying compounds capable of inhibiting VR1 are known tothose skilled in the art, for example, those methods disclosed in U.S.Pat. No. 6,239,267 to Duckworth et al.; U.S. Pat. No. 6,406,908 toMcIntyre et al.; or U.S. Pat. No. 6,335,180 to Julius et al. The resultsof these assays will demonstrate that Cycloheteroalkenyl Compounds bindto and modulate the activity of VR1.

Binding of Compound A19(c) to VR1: Assay Protocol

Human VR1 Cloning:

Human spinal cord RNA (commercially available from Clontech, Palo Alto,Calif.) was used. Reverse transcription was conducted on 1.0 μg totalRNA using Thermoscript Reverse Transcriptase (commercially availablefrom Invitrogen, Carlsbad, Calif.) and oligo dT primers as detailed inits product description. Reverse transcription reactions were incubatedat 55° C. for 1 h, heat-inactivated at 85° C. for 5 min, and RNaseH-treated at 37° C. for 20 min.

Human VR1 cDNA sequence was obtained by comparison of the human genomicsequence, prior to annotation, to the published rat sequence. Intronsequences were removed and flanking exonic sequences were joined togenerate the hypothetical human cDNA. Primers flanking the coding regionof human VR1 were designed as follows: forward primer,GAAGATCTTCGCTGGTTGCACACTGGGCCACA; and reverse primer,GAAGATCTTCGGGGACAGTGACGGTTGGATGT.

PCR of VR1 was performed on one tenth of the Reverse transcriptionreaction mixture using Expand Long Template Polymerase and Expand Buffer2 in a final volume of 50 μL according to the manufacturer'sinstructions (Roche Applied Sciences, Indianapolis, Ind.). Afterdenaturation at 94° C. for 2 min PCR amplification was performed for 25cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68° C. for 3 minfollowed by a final incubation at 72° C. for 7 min to complete theamplification. A PCR product of ˜2.8 kb was gel-isolated using a 1.0%agarose, Tris-Acetate gel containing 1.6 μg/mL of crystal violet andpurified with a S.N.A.P. UV-Free Gel Purification Kit (commerciallyavailable from Invitrogen). The VR1 PCR product was cloned into thepIND/V5-His-TOPO vector (commercially available from Invitrogen)according to the manufacturer's instructions. DNA preparations,restriction enzyme digestions, and preliminary DNA sequencing wereperformed according to standard protocols. Full-length sequencingconfirmed the identity of the human VR1.

Generation of Inducible Cell Lines:

Unless noted otherwise, cell culture reagents were purchased from LifeTechnologies of Rockville, Md. HEK293-EcR cells expressing the ecdysonereceptor (commercially available from Invitrogen) were cultured inGrowth Medium (Dulbecco's Modified Eagles Medium containing 10% fetalbovine serum (commercially available from HYCLONE, Logan, Utah), 1×penicillin/streptomycin, 1× glutamine, 1 mM sodium pyruvate and 400μg/mL Zeocin (commercially available from Invitrogen)). The VR1-pINDconstructs were transfected into the HEK293-EcR cell line using Fugenetransfection reagent (commercially available from Roche AppliedSciences, Basel, Switzerland). After 48 h, cells were transferred toSelection Medium (Growth Medium containing 300 μg/mL G418 (commerciallyavailable from Invitrogen)). Approximately 3 weeks later individualZeocin/G418 resistant colonies were isolated and expanded. To identifyfunctional clones, multiple colonies were plated into 96-well plates andexpression was induced for 48 h using Selection Medium supplemented with5 μM ponasterone A (“PonA”) (commercially available from Invitrogen). Onthe day of assay, cells were loaded with Fluo-4 (a calcium-sensitive dyethat is commercially available from Molecular Probes, Eugene, Oreg.) andCAP-mediated calcium influx was measured using a FLIPR as describedbelow. Functional clones were re-assayed, expanded, and cryopreserved.

pH-Based Assay:

Two days prior to performing this assay, cells were seeded onpoly-D-lysine-coated 96-well clear-bottom black plates (commerciallyavailable from Becton-Dickinson) at 75,000 cells/well in growth mediacontaining 5 μM PonA (commercially available from Invitrogen) to induceexpression. On the day of the assay, the plates were washed with 0.2 mL1× Hank's Balanced Salt Solution (commercially available from LifeTechnologies) containing 1.6 mM CaCl₂ and 20 mM HEPES, pH 7.4 (“washbuffer”), and loaded using 0.1 mL of wash buffer containing Fluo-4 (3 μMfinal concentration, commercially available from Molecular Probes).After 1 h, the cells were washed twice with 0.2 mL wash buffer andresuspended in 0.05 mL 1× Hank's Balanced Salt Solution (commerciallyavailable from Life Technologies) containing 3.5 mM CaCl₂ and 10 mMCitrate, pH 7.4 (“assay buffer”). Plates were then transferred to aFLIPR for assay. Compound A19(c) was diluted in assay buffer, and 50 mLof the resultant solution were added to the cell plates and the solutionmonitored for two minutes. The final concentration of Compound A19(c)ranged from about 50 pM to about 3 μM. Agonist buffer (wash buffertitrated with 1N HCl to provide a solution having a pH of 5.5 when mixed1:1 with assay buffer) (0.1 mL) was then added to each well, and theplates were incubated for 1 additional minute. Data were collected overthe entire time course and analyzed using Excel and Graph Pad Prism.Compound A19(c) when assayed according to this protocol had an IC₅₀ of735 nM.

Capsaicin-Based Assay:

Two days prior to performing this assay, cells were seeded inpoly-D-lysine-coated 96-well clear-bottom black plates (50,000cells/well) in growth media containing 5 μM PonA (commercially availablefrom Invitrogen) to induce expression. On the day of the assay, theplates were washed with 0.2 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 1 mM CaCl₂and 20 mM HEPES, pH 7.4, and cells were loaded using 0.1 mL of washbuffer containing Fluo-4 (3 μM final). After one hour, the cells werewashed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL ofwash buffer. The plates were transferred to a FLIPR for assay. 50 μL ofCompound A19(c) diluted with assay buffer were added to the cell platesand incubated for 2 min. The final concentration of Compound A19(c)ranged from about 50 pM to about 3 μM. Human VR1 was activated by theaddition of 50 μL of capsaicin (400 nM), and the plates were incubatedfor an additional 3 min. Data were collected over the entire time courseand analyzed using Excel and GraphPad Prism. Compound A19(c) whenassayed according to this protocol had an IC₅₀ of 19 nM.

The results of the pH-based assay and the capsaicin-based assaydemonstrate that Compound A19(c), an illustrative CycloheteroalkenylCompound, binds to and modulates the activity of human VR1.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichare incorporated herein by reference.

1-28. (canceled)
 29. A method of treating pain in an animal, comprisingadministering to an animal in need thereof an effective amount of acompound of formula (I), or a pharmaceutically acceptable salt thereof,the compound of formula (I) having the structure:

wherein Ar₁ is

Ar₂ is

X is O, S, N—CN, N—OH, or N—OR₁₀; R₁ is —H, -halo, —CH₃, —NO₂, —CN, —OH,—OCH₃, —NH₂, —C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₂ isindependently: (a) -halo, —OH, —CN, or —NO₂; (b) —(C₁-C₁₀)alkyl,—(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃-C₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups; or(c) -phenyl, -naphthyl, —(C₁₄)aryl or -(5- to 10-membered)heterocycle,each of which is unsubstituted or substituted with one or more R₆groups; each R₃ is independently: (a) -halo, —CN, —OH, —NO₂, or —NH₂;(b) —(C₁-C₁₀)alkyl, —(C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl,—(C₃-C₁₀)cycloalkyl, —(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl,—(C₅-C₁₀)cycloalkenyl, —(C₈-C₁₄)bicycloalkenyl,—(C₈-C₁₄)tricycloalkenyl, -(3- to 7-membered)heterocycle or -(7- to10-membered)bicycloheterocycle, each of which is unsubstituted orsubstituted with one or more R₅ groups; or (c) -phenyl, -naphthyl,-(C₁₄)aryl or -(5- to 10-membered)heterocycle, each of which isunsubstituted or substituted with one or more R₆ groups; each R₅ isindependently —CN, —OH, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, -halo, —N₃,—NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇,—OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; each R₆ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇; each R₇ is independently —H, —(C₁-C₆)alkyl,—(C₂₋₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle,—C(halo)₃, —CH(halo)₂, or —CH₂(halo); each R₈ is independently—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —(C₃-C₈)cycloalkyl,—(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN,—OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇,—OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or —S(O)₂R₇; R₁₀ is —(C₁-C₄)alkyl;each R₁₁ is independently —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₁-C₆)alkynyl, —(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl,—C(halo)₃, —CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂,—CH═NR₇, —NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇,—S(O)R₇, or —S(O)₂R₇; each halo is independently —F, —Cl, —Br, or —I; mis 0 or 1; o is an integer ranging from 0 to 4; p is an integer rangingfrom 0 to 2; q is an integer ranging from 0 to 6; s is an integerranging from 0 to 4; and r is an integer ranging from 0 to
 5. 30-32.(canceled)
 33. The method of claim 29, wherein Ar₂ is

wherein R₈ and s are as defined in claim
 29. 34. The method of claim 33,wherein Ar₂ is

wherein (R₈)_(a) and (R₈)_(b) are each —H or —(C₁-C₆ alkyl); (R₈)_(a) is—H and (R₈)_(b) is —(C₁-C₆)alkyl, -halo, —C(halo)₃, —O(C₁-C₆)alkyl, or—OC(halo)₃; or (R₈)_(b) is —H and (R₈)_(a) is —(C₁-C₆)alkyl, -halo,—C(halo)₃, —O(C₁-C₆)alkyl, or —OC(halo)₃.
 35. The method of claim 34,wherein X is O; (R₈)_(a) and (R₈)_(b) are each —H or —CH₃; (R₈)_(a) is—H and (R₈)_(b) is —(C₁-C₆)alkyl, -halo, —CF₃, —OCH₃, —OCH₂CH₃, or—OCF₃; or (R₈)_(b) is —H and (R₈)_(a) is —Cl, —Br, —F, —CH₃,-iso-propyl, -tert-butyl, —CF₃, —OCH₃, —OCH₂CH₃, or —OCF₃.
 36. Themethod of claim 34, wherein X is O, p and m are each 0, R₁ is hydrogen,halo, —CH₃, —NO₂, —CN, —OH, —CF₃, or —CHF₂.
 37. The method of claim 34,wherein (R₈)_(a) is —H and (R₈)_(b) is —(C₁-C₆)alkyl or -halo.
 38. Themethod of claim 37, wherein (R₈)_(b) is an iso-propyl group or atert-butyl group.
 39. The method of claim 29, wherein m is
 0. 40. Themethod of claim 29, wherein R₁ is -halo, —CH₃, or —C(halo)₃.
 41. Themethod of claim 29, wherein p is 1 and R₂ is -halo, —OH, —NH₂, —CN, or—NO₂.
 42. The method of claim 29, wherein p is 1, and R₂ is—(C₁-C₁₀)alkyl, (C₂-C₁₀)alkenyl, —(C₂-C₁₀)alkynyl, —(C₃₋₁₀)cycloalkyl,—(C₈-C₁₄)bicycloalkyl, —(C₈-C₁₄)tricycloalkyl, —(C₅-C₁₀)cycloalkenyl,—(C₈-C₁₄)bicycloalkenyl, —(C₈-C₁₄)tricycloalkenyl, -(3- to7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, eachof which is unsubstituted or substituted with one or more R₅ groups. 43.The method of claim 29, wherein m is 1 and R₃ is -halo, —CN, —OH, —NO₂,or —NH₂.
 44. The method of claim 29, wherein m is 1 and R₃ is —CH₃. 45.The method of claim 29, wherein Ar₂ is

o is 1; and R₈ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇.
 46. The method of claim 29, wherein Ar₂ is

o is 1; and R₈ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇.
 47. The method of claim 29, wherein Ar₂ is

r is 1; and R₈ is —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₈)cycloalkyl, —(C₅-C₈)cycloalkenyl, -phenyl, —C(halo)₃,—CH(halo)₂, —CH₂(halo), —CN, —OH, -halo, —N₃, —NO₂, —N(R₇)₂, —CH═NR₇,—NR₇OH, —OR₇, —COR₇, —C(O)OR₇, —OC(O)R₇, —OC(O)OR₇, —SR₇, —S(O)R₇, or—S(O)₂R₇.
 48. The method of claim 29, wherein X is O, m is 0, and Ar₂ is


49. The method of claim 48, wherein r is 1, Ar₂ is substituted at the4-position, p is zero, m is zero, R₁ is hydrogen, halo, —CH₃, —NO₂, —CN,—OH, —C(halo)₃, —CH(halo)₂, or —CH₂(halo), and R₈ is halo,—(C₁-C₆)alkyl, —OC(halo)₃, —O(C₁-C₆)alkyl, —(C₃-C₈)cycloalkyl, or—C(halo)₃.
 50. The method of claim 49, wherein R₁ is halo.
 51. Themethod of claim 50, wherein R₁ is F.
 52. The method of claim 49, whereinR₁ is hydrogen, halo, —CH₃, —NO₂, —CN, —OH, —CF₃, —CHF₂, or —CH₂F. 53.The method of claim 29, wherein said pain is chronic pain.
 54. Themethod of claim 29, further comprising administering an effective amountof an opioid agonist.
 55. The method of claim 29, further comprisingadministering an effective amount of a non-opioid analgesic.
 56. Themethod of claim 29, further comprising administering an effective amountof an agent for inhibiting vomiting.